Biogentic amine uptake inhibitors

ABSTRACT

Compounds of the formula: ##STR1## or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2 and n is 0 or 1; 
     R 1  is hydrogen or lower alkyl; 
     R 2  is C 1  -C 6  -alkyl substituted with a heterocyclic group or C 7  -C 16  -arylalkyl, wherein the aryl group is unsubstituted or substituted with from one to three non-hydrogen members independently selected from the group consisting of halogen, C 1  -C 6  -alkyl, halo-C 1  -C 6  -alkyl, C 1  -C 6  -alkoxy, hydroxy, amino and C 1  -C 6  -alkylamino; 
     R 3 , R 4 , R 5  and R 6  are independently selected from the group consisting of hydrogen, C 1  -C 6  -alkoxy, C 1  -C 6  -alkyl, halogen, and halo-C 1  -C 6  -alkyl, or any two of R 3 , R 4 , R 5  and R 6  taken together form a methylenedioxy group; and 
     R 7  is hydrogen or C 1  -C 6  -alkyl. 
     These compounds are useful as inhibitors of the neuronal uptake of biogenic amines and for the treatment of affective disorders, such as, for example, depression.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.07/672,011, filed Mar. 22, 1991, now U.S. Pat. No. 5,180,733, which is acontinuation-in-part of U.S. application Ser. No. 07/570,234, filed Aug.20, 1990, now abandoned, which is a continuation-in-part of U.S.application Ser. No. 07/502,601, filed Mar. 30, 1990, now abandoned.

TECHNICAL FIELD

This invention relates to novel compounds and compositions thereof whichinhibit neuronal biogenic amine uptake, to processes for making suchcompounds, to synthetic intermediates employed in these processes and toa method of treating affective disorders, such as, for example,depression, with such compounds.

BACKGROUND OF THE INVENTION

Disturbances of mood (affective disorders: cf, R. J. Baldessarini inGoodman and Gillman's The Pharmacological Basis of Therapeutics. A. G.Gilman, L. S. Goodman, T. W. Rall and F. Murad, Eds., Macmillan, NewYork, 1985, pp 412-432) are the most common psychiatric disorders inadults. It has been estimated that 18-23% of women and 8-11% of men inthe United States experience at least one major depressive episode intheir lifetimes. Unfortunately, there are major drawbacks to the use ofcurrently available agents for treating affective disorders. Forexample, no antidepressant drug to date has proven to be superior toelectroconvulsive shock therapy in the treatment of severe, suicidaldepression. Other problems with the use of the various available drugsare delayed onset of activity, poor efficacy, anticholinergic effects attherapeutic doses, cardiotoxicity, convulsions and the danger of takinga fatal overdose. There also exists a large number of untreatedindividuals and treatment-resistant patients in need of effectivetherapy.

It is now recognized that depressive conditions may result from reducedamounts of certain biogenic amine neurotransmitters such asnoradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the centralnervous system (CNS). Therapeutic agents can theoretically raise thesynaptic levels of these biogenic amine neurotransmitters in the CNS bytwo principal mechanisms: by inhibition of the neuronal uptake of thebiogenic amine neurotransmitters and by inhibition of the metabolicenzymes responsible for converting the biogenic amines to inactivemetabolites, such as, for example, monoamine oxidase (MAO). Biogenicamine uptake inhibitors, including classical antidepressants such asimipramine, desipramine and amitriptyline, as well as newernon-classical agents such as fluoxetine (Prozac) are well known to betherapeutically useful in the treatment of affective disorders such asdepression, and related CNS disorders. These clinically-effective agentsexert their therapeutic effect through the inhibition of the uptake ofbiogenic amines into neuronal terminals in the CNS, cf: R. W. Fuller, inAntidepressants: Neurochemical, Behavioral and Clinical Perspectives, S.J. Enna, J. D. Malick, and E. Richelson, Eds, Raven Press, New York,1981, pp 1-12; L. E. Hollister, Drugs 1981, 22:129; J. Schildkraut inPsychopharmacology: A Generation of Progress, A. M. Lipton, A. DiMascioand K. F. Killam, Eds, Raven Press, New York, 1978, pp 1223-1234; F.Sulser in Typical and Atypical Antidepressants:Molecular Mechanisms, E.Costa and G. Racagni, Eds., Raven Press, New York, 1982, pp 1-20; W.Kostowski, Trends Pharmacol. Sci. 1981, 2:314; J. Maj, Trends Pharmacol.Sci. 1981, 2:80; and C. Kaiser and P. E. Setler in Burger's MedicinalChemistry, 4th ed., M. E. Wolff, Ed., Wiley, New York, 1979, Part III,pp 997-1067.

The novel compounds of the present invention are potent inhibitors ofbiogenic amine neuronal uptake. Other tetrahydrobenz[e]isoindolines andoctahydrobenz[h]isoquinolines, which have distinctly different or noknown utility, are disclosed by J. F. DeBernardis, et al., U.S. Pat. No.4,618,683, issued Oct. 21, 1986; by J. G. Cannon, et al., J. Med. Chem.,1980, 23:502-505; and by W. Oppolozer, Tetrahedron Letters, 1974,1001-4.

SUMMARY OF THE INVENTION

The present invention is directed to compounds that inhibit neuronalbiogenic amine uptake of the formula (I): ##STR2## orpharmaceutically-acceptable salts thereof, wherein m is 0, 1 or 2 and nis 0 or 1;

R¹ is hydrogen or C₁ -C₆ -alkyl;

R² is selected from C₁ -C₆ -alkyl substituted with a heterocyclic group,and C₇ -C₁₆ -arylalkyl, wherein the aryl group is unsubstituted orsubstituted with from one to three non-hydrogen members independentlyselected from the group consisting of halogen, C₁ -C₆ -alkyl, halo-C₁-C₆ -alkyl, C₁ -C₆ -alkoxy, hydroxy, amino and C₁ -C₆ -alkylamino;

R³, R⁴, R⁵ and R⁶ are independently selected from hydrogen, C₁ -C₆-alkoxy, C₁ -C₆ -alkyl, halogen and halo-C₁ -C₆ -alkyl, or any two ofR³, R⁴, R⁵ and R⁶ taken together form a methylenedioxy group; and

R⁷ is hydrogen or C₁ -C₆ -alkyl.

The present invention is also directed to pharmaceutical compositionscomprising a therapeutically-effective amount of a compound of theformula (I) and a pharmaceutically-acceptable carrier or diluent, aswell as to a method of treating depression and related affectivedisorders in humans and lower mammals, by administration of a compoundof formula (I).

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel compounds of formula (I) which areselective inhibitors of the neuronal uptake of biogenic amines and,therefore, may be used in the treatment of affective disorders, such as,for example, depression.

In particular, the invention relates to compounds of the formula (I):##STR3## or pharmaceutically-acceptable salts thereof, wherein m is 0, 1or 2 and n is 0 or 1;

R¹ is hydrogen or C₁ -C₆ -alkyl;

R² is selected from C₁ -C₆ -alkyl substituted with a heterocyclic group,and C₇ -C₁₆ -arylalkyl, wherein the aryl group is unsubstituted orsubstituted with from one to three non-hydrogen members independentlyselected from the group consisting of halogen, C₁ -C₆ -alkyl, halo-C₁-C₆ -alkyl, C₁ -C₆ -alkoxy, hydroxy, amino and C₁ -C₆ -alkylamino;

R³, R⁴, R⁵ and R⁶ are independently selected from hydrogen, C₁ -C₆-alkoxy, C₁ -C₆ -alkyl, halogen and halo-C₁ -C₆ -alkyl, or any two ofR³, R⁴, R⁵ and R⁶ taken together form a methylenedioxy group; and

R⁷ is hydrogen or C₁ -C₆ -alkyl.

In one embodiment of the present invention, represented by formula (IA),m and n are both 0 and R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as definedabove: ##STR4##

In a second embodiment of the present invention, represented by formula(IB), m is 0, n is 1 and R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as definedabove: ##STR5## In another embodiment of the present invention,represented by formula (IC), m is 1, n is 0 and R¹, R², R³, R⁴, R⁵, R⁶and R⁷ are as defined above: ##STR6## In yet another embodiment of thepresent invention, represented by formula (ID), m is 2, n is 0 and R¹,R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above: ##STR7##

The term "C₁ -C₆ -alkoxy" refers to a lower alkyl group, as definedbelow, which is bonded through an oxygen atom. Examples of lower alkoxygroups are methoxy, ethoxy, isoprpoxy, t-butoxy, and the like.

The term "alkoxyalkyl" as used herein refers to C₁ -C₆ -alkyl groups, asdefined below, which are substituted with an C₁ -C₆ -alkoxy group asdefined below.

The term "C₁ -C₆ -alkyl" refers to branched or straight chain alkylgroups comprising one to six carbon atoms including, but not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyland the like.

The term "C₇ -C₁₆ -arylalkyl" is used herein to mean straight orbranched chain radicals of one to six carbon atoms which are substitutedwith benzene, naphthalene, alkyl, halogen, methoxy, N-methyl or with abenzoheterocycle, as defined below.

The term "benzoheterocycle" is used hereinabove to mean a heterocycle towhich is fused a benzene ring, such as, for example, 1,3-benzodioxole,1,4-benzodioxan, indolyl, indolinyl, benzofuryl, benzothienyl,benzimidazolyl, quinolyl, isoquinolyl, dihydroisoquinolyl,tetrahydroisoquinolyl, and the like. Benzoheterocycles are attached tothe alkyl radical through one of the carbon atoms of the heterocycle.

The term "halo-C₁ -C₆ -alkyl" refers to a C₁ -C₆ -alkyl group, asdefined below, bearing at least one halogen substituent, for examplefluoromethyl, chloromethyl, bromomethyl, dichloroethyl, trifluoromethyl,and the like.

The term "halogen" as used herein refers to bromo (Br), chloro (Cl),fluoro (F) and iodo (I).

The term heterocycle" or "heterocyclic group" as used herein refers to a5-, 6- or 7-membered ring, wherein one, two or three nitrogen atoms, onesulfur atom, one nitrogen and one sulfur atom, two nitrogen and onesulfur atom, one oxygen atom, or one nitrogen and one oxygen atomreplace from one to three of the carbon atoms, and the 5-membered ringhas from 0 to 2 double bonds and the 6-membered ring has from 0 to 3double bonds. Heterocyclic groups include, but are not limited to,N-methylpyrrolyl, pyridyl, pyrimidinyl, furyl, thienyl,N-methylpyrazolyl, oxazolyl, isoxazolyl, 1,2,4-triazolyl, thiadiazolyl,tetrahydrofuryl, N-methylimidazolyl, N-methyl-piperazinyl, peperidinyl,pyrrolidinyl, thiazolyl, isoxazolinyl, and the like.

The following compounds are representative of the compounds of formula(I):

cis/trans2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-phenylethyl-3-phenylmethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-(3-chlorophenyl)ethyl-3-phenylmethyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

cis-anti-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-1H-benz[e]isoindole;

cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-1H-benz[e]isoindole;

cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindole;cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindole;

3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindole;

cis-3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-3-(3-methoxyphenyl)methyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-3-(3-methoxyphenyl)methyl-2-methyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-6-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindole;

cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-2-methyl-1H-benz[e]isoindole;

cis-2-Ethyl-3-(3-fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benz[e]isoindole;

trans-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-1H-benz[e]isoindole;

trans-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-2-methyl-1H-benz[e]isoindole;

cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-2-methyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-(3-methoxyphenyl)methyl-2-methyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-(3-phenyl-1-propyl)-1H-benz[e]isoindole;

cis-5,6-Dimethoxy-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-1H-benz[e]isoindole;

cis-6,7-Dimethoxy-2,3,3a,4,5,9b-hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

trans-6,7-Dimethoxy-2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindole;

trans-6,7-Dimethoxy-2,3,3a,4,5,9b-hexahydro-2-methyl-3-(3-methylphenyl)methyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-6,7-methylenedioxy-3-(3-methylphenyl)methyl-1H-benz[e]isoindole;

trans-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7-methylenedioxy-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-6-methoxy-9-methyl-3-phenylmethyl-1H-benz[e]isoindole;

cis-2,9-Dimethyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindole;

cis-2-Ethyl-9-(4-(4-fluorophenyl)butyloxy)-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindole;

trans-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7,8-trimethoxy-1H-benz[e]isoindole;

3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7,9-trimethoxy-1H-benz[e]isoindole;

6,7-Dimethoxy-9-fluoro-3-(3-fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindole;

cis-7-Bromo-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-1H-benz[e]isoindole;

cis-7-Bromo-2,3,3a,4,5,9b-hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

cis-3-(2-Chloro-5-N-ethyl-N-methylaminophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindole;

3-(3-Chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindole;

3-(3-Chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindole;

trans-7-Chloro-3-(3-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindole;

cis-7-Chloro-3-(3-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindole;

1,2,3,4,4a,5,6,10b-Octahydro-4-phenylmethyl-benz[f]isoquinoline;

cis-2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline;

trans-2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline;

8-Methoxy-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline;

cis-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline;

cis/syn-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline;

(+)-cis/anti-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline;

(-)-cis/anti-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline;

(+)-cis/syn-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline;

(-)-cis/syn-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline;

(-)-trans/syn8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline;

(+)-trans/syn8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline;

2-Ethyl-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline;

2-Ethyl-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline;

2,10b-Diethyl-8-ethoxy-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline;

2,3,3a,4,5,9b-Hexahydro-2-methyl-6,7-methylenedioxy-3-(2-thienyl)methyl-1H-benz[e]isoindole;

3-(2-Furanyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7-methylenedioxy-1H-benz[e]isoindole;

3-(2-Cyclopentadienyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7-methylenedioxy-1H-benz[e]isoindole;

2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(N-methyl-2-pyrolyl)methyl-6,7-methylenedioxy-1H-benz[e]isoindole;

2,3,3a,4,5,9b-Hexahydro-2-methyl-6,7-methylenedioxy-3-(2-pyridinyl)methyl-1H-benz[e]isoindole;

3-(1,3-Dioxalan-2-yl)-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7-methylenedioxy-1H-benz[e]isoindole;

9-Fluoro-2,3,3a,4,5,9b-hexahydro-6,7-methylenedioxy-3-phenylmethyl-1H-benz[e]isoindole;

9-Fluoro-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7-methylenedioxy-3-phenylmethyl-1H-benz[e]isoindole;

9-Fluoro-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7-methylenedioxy-3-(2-thienyl)methyl-1H-benz[e]isoindole;

9-Fluoro-3-(2-furanyl)methyl-2,3,3a,4,5,9b-hexahydro-2methyl-6,7-methylenedioxy-1H-benz[e]isoindole;

9-Fluoro-2,3,3a,4,5,9b-hexahydro-2-methyl-3-(N-methyl-2-pyrolyl)methyl-6,7-methylenedioxy-1H-benz[e]isoindole;

9-Fluoro-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7-methylenedioxy-3-(2-pyridinyl)methyl-1H-benz[e]isoindole;

3-(1,3-Dioxalan-2-yl)-9-fluoro-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7-methylenedioxy-1H-benz[e]isoindole;

2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline;

8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline;

2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine;

8-Methoxy-2-methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine;

cis/trans2,3,3a,4,5,9b-Hexahydro-3-phenylmethyl-6-trifluoromethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-6-trifluoromethyl-1H-benz[e]isoindole;

cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-6-trifluoromethyl-1H-benz[e]isoindole;

cis/trans2,3,3a,4,5,9b-Hexahydro-3-phenylmethyl-7-trifluoromethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-7-trifluoromethyl-1H-benz[e]isoindole;

cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-7-trifluoromethyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-3-phenylmethyl-6-trifluoromethyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-6-trifluoromethyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-3-phenylmethyl-7-trifluoromethyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-7-trifluoromethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-3-(3-methylphenyl)methyl-6-trifluoromethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-6-trifluoromethyl-1H-benz[e]isoindole;

cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-6-trifluoromethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-3-(3-methylphenyl)methyl-7-trifluoromethyl-1H-benz[e]isoindole;

cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-7-trifluoromethyl-1H-benz[e]isoindole;

cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-7-trifluoromethyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-6-trifluoromethyl-1H-benz[e]isoindole;

trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-7-trifluoromethyl-1H-benz[e]isoindole;

cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-trifluoromethyl-1H-benz[e]isoindole;

cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6-trifluoromethyl-1H-benz[e]isoindole;

cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-trifluoromethyl-1H-benz[e]isoindole;

cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-7-trifluoromethyl-1H-benz[e]isoindole;

3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-trifluoromethyl-1H-benz[e]isoindole;

cis-3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6-trifluoromethyl-1H-benz[e]isoindole;

3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-trifluoromethyl-1H-benz[e]isoindole;

cis-3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-7-trifluoromethyl-1H-benz[e]isoindole;

(+)-cis-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine;

(-)-cis-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine;

trans-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine;

as well as pharmaceutically-acceptable salts thereof.

The following compounds are representative of the preferred compounds offormula (I):

2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

2-Ethyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindole;

2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-1H-benz[e]isoindole;

2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindole;

3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindole;

2,3,3a,4,5,9b-Hexahydro-6-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

2-Ethyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindole;

3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-2-methyl-1H-benz[e]isoindole;

2-Ethyl-3-(3-fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benz[e]isoindole;

3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-2-methyl-1H-benz[e]isoindole;

5,6-Dimethoxy-2,3,3a,4,5,9b-hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindole;

3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7-methylenedioxy-1H-benz[e]isoindole;

2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline;

8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline;

2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine;and

8-Methoxy-2-methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine;

(-)-cis-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride;

as well as pharmaceutically-acceptable salts thereof.

The following compounds are representative of the more preferredcompounds of formula (I):

2-Ethyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindole;

2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindole;

2-Ethyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindole;

2-Ethyl-3-(3-fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benz[e]isoindole;

2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline;

2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine;and

8-Methoxy-2-methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine;

(-)-cis-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride;

as well as pharmaceutically-acceptable salts thereof.

Certain compounds of this invention exist in optically active forms. Thepure d isomers and pure/isomers, as well as mixtures thereof includingthe racemic mixtures, are contemplated by this invention. Additionalasymmetric centers may be present in a substituent such as an alkylgroup. All such isomers as well as mixtures thereof are intended to bewithin the scope of this invention. In particular, stereochemistry ofthe hydrogen atoms and substituents at the ring junction and at thecarbon to which R² is attached, as shown in formula (I), canindependently be either axial or equatorial unless specifically notedotherwise.

The compounds of this invention are synthesized by reaction schemes IAthrough VII illustrated below. It should be understood that R¹ -R⁷ asused herein correspond to the R groups identified by formula (I). Thereactions are performed in a solvent appropriate to the reagents andmaterials employed are suitable for the transformation being effected.It is understood by those skilled in the art of organic synthesis thatthe functionality present on the phenyl ring and other portions of themolecule must be consistent with the chemical transformation proposed.This will, on occasion, necessitate judgment as to the order ofsynthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to skilled practitioners inthe art. The use of amino-protecting groups is well known in the art forprotecting amino groups against undesirable reactions during a syntheticprocedure and many such protecting groups are known, c.f., T. H. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York(1981). ##STR8##

Scheme IA

According to reaction scheme 1A, the unsaturated nitriles of Formula 2are prepared by Lewis acid catalyzed trimethylsilyl cyanide addition toknown tetralones of Formula 1, followed by acid-catalyzed elimination ofthe intermediate adduct. The conjugate addition of2-lithio-2-substituted-1,3-dithianes of the Formula 3 to the unsaturatednitriles of Formula 2 affords the 1,4-Michael addition products ofFormula 4 as a mixture of cis and trans isomers. The mercuric chloridecatalyzed dithiane-ketal exchange in ethylene glycol/THF at refluxaffords the corresponding ketals of Formula 5.

The reduction of the nitriles of Formula 5 to the aminomethyl compoundsof Formula 6 is accomplished by catalytic hydrogenation with a suitablecatalyst such as Raney nickel in a suitable solvent, such as methanol orby treatment with a suitable reducing agent, such as, for example,lithium aluminum hydride. The desired benzoisoindolines of Formula 7 areobtained in a one pot reaction from the hydrolysis of aminomethyl ketalsof Formula 6 with a suitable acid, such as hydrochloric acid, in a polarsolvent such as THF, to the keto-amine. The keto-amine is in equilibriumwith the corresponding iminium compound which is readily reduced bysodium cyanoborohydride. The compounds of Formula 7 are converted to theN-alkylated compounds of Formula IA by alkylation under standardconditions, such as hydrogenation in the presence of a suitable catalystsuch as palladium on carbon (Pd/C), and a suitable carbonyl compound,such as, for example, formaldehyde. ##STR9##

Scheme IB

According to reaction scheme IB, the 1,4-Michael addition products ofFormula 4 are hydrolyzed to the corresponding ketones of Formula 8 withmercuric chloride and a suitable base, such as calcium carbonate, in asuitable polar solvent, such as acetonitrile/water. Reduction of theketo-nitriles of Formula 8, for example, by hydrogenation with asuitable catalyst such as Raney nickel in a polar solvent such asmethanol, in the presence of a suitable base, such as triethylamine,affords the isoindoline compounds of Formula 7, predominantly as thetrans isomer. The compounds of Formula 7 are converted to theN-alkylated compounds of Formula IA by alkylation under standardconditions such as hydrogenation in the presence of a suitable catalyst,such as palladium on carbon, and a suitable carbonyl compound such asformaldehyde. Alternately, they may be alkylated by treatment with analkylating agent, such as dimethyl sulfate or methyl iodide, in thepresence of a suitable base, such as sodium hydide, sodium ethoxide orpotassium carbonate, in a suitable solvent. ##STR10##

Scheme IC

According to reaction scheme IC, the compounds of Formula 4 are reducedto the aminomethyl dithiane derivatives of Formula 9 with a suitablereducing agent, such as, for example, diborane in THF. The resultingamino compounds of Formula 9 are acylated with a suitable acylatingagent, such as acetic anhydride, in a suitable base such as pyridine, toyield the N-acetyl compounds of Formula 10. N-bromosuccinimide (NBS)catalyzed dithiane hydrolysis of compounds of the Formula 10 in a polarsolvent, such as acetone/water or acetonitrile/water, affords thecorresponding N-protected keto-amine compounds of Formula 11. Hydrolysisof N-acetyl group of compounds of Formula 10 with a suitable acid suchas aqueous hydrochloric acid, followed by intramolecular reductiveamination, affords the isoindoline compounds of Formula 7. The compoundsof Formula 7 are converted to the N-alkylated compounds of Formula IA byalkylation under standard conditions, such as hydrogenation in thepresence of a suitable catalyst, such as palladium on carbon, and asuitable carbonyl compound such as formaldehyde, or by treatment with analkylating agent, such as dimethyl sulfate or methyl iodide, in thepresence of a suitable base, such as sodium hydide, sodium ethoxide orpotassium carbonate, in a suitable solvent. ##STR11##

Scheme II

According to reaction scheme II, the unsaturated nitriles of Formula 2are converted to the corresponding unsaturated esters by treatment witha suitable acid, such as sulfuric acid, in a suitable alcohol solvent,for example methanol which gives the methyl esters of Formula 12. Anunsaturated ester of Formula 12 is, in turn, reacted with a nitromethanederivative of Formula 13 to afford an adduct of Formula 14. The adductsof Formula 14 are cyclized to the compounds of Formula 15 by treatmentwith a suitable reducing agent for reducing the nitro group withoutreducing the ester, for example zinc and acetic acid. The lactams ofFormula 15 are reduced to the isoindoline compounds of Formula 7 with asuitable reducing agent, such as, for example, borane. The compounds ofFormula 7 are converted to the N-alkylated compounds of Formula IA byalkylation under standard conditions, such as hydrogenation in thepresence of a suitable catalyst, such as palladium on carbon, and asuitable carbonyl compound such as formaldehyde or by treatment with analkylating agent, such as dimethyl sulfate or methyl iodide, in thepresence of a suitable base, such as sodium hydide, sodium ethoxide orpotassium carbonate, in a suitable solvent. ##STR12##

Scheme III

According to the reaction scheme III, the conjugate addition of thecompounds of Formula 16 (wherein R² may not be substituted with halogen)with the unsaturated nitrile of Formula 2 (wherein R³, R⁴, R⁵ and R⁶ maynot be halogen) yields the dinitriles of Formula 17 as a mixture of thecis and trans isomers. Hydrolysis of compounds of Formula 17 with asuitable acid, such as hydrobromic acid in methylene chloride, followedby DMF/water affords the cis imido compounds of Formula 18. Reduction ofthe cis imido compounds of Formula 16 with a suitable reducing agent,such as diborane in THF, affords the desired isoquinolines of FormulasIB1. Alternately compounds of Formula 17, wherein any of any or all ofR³, R⁴, R⁵ or R⁶ are methoxy, are cyclized to compounds of Formula 18 ina suitable acid, for example, a mixture of sulfuric and acetic acids, inwhich the methoxy group has been hydrolyzed to a hydroxy group. Thesecompounds, in turn are converted to compounds of Formula 19 by standardalkylation procedures. Reduction of the imido compounds of Formula 19 iscarried out as discussed above for compounds of Formula 16 to afford thecompounds of Formula IB2.

Compounds of Formula 18 in which R² is hydrogen are alkylated bytreatment with a suitable alkylating agent such as methyl iodide ordimethylsulfate in the presence of a suitable base, for example,potasium or sodium t-butoxide or sodium hydride, to afford the compoundsof Formula 20. The compounds of Formula 20 are, in turn, treatedsequentially with a Grignard reagent, such as benzyl magnesium bromide,mild acid, for example, hydrochloric acid in methanol, and sodiumcyanoborohydride to afford the compounds of Formula IC. ##STR13##

Scheme IV

According to reaction scheme IV, an unsaturated nitrile of Formula 2 iscondensed with an acetate ester, for example ethyl acetate, in thepresence of a suitable base, such as diisopropylamide (LDA), to affordthe adducts of Formula 21. The compounds of Formula 21 are cyclized tothe compounds of Formula 22 by reduction of the nitrile group to theaminomethyl group. The reduction can be carried out by catalytichydrogenation or by treatment with a suitable reducing agent, such as,for example lithium aluminum hydride. The lactams of Formula 22 arealkylated by standard alkylation procedures, for example, treatment withmethyl iodide in the presence of a suitable base, such as potassiumt-butoxide, to afford the compounds of Formula 23. The compounds ofFormula 23 are treated sequentially with a Grignard reagent, forexample, benzylmagnesium chloride, a mild acid, such as methanolichydrogen chloride, and a suitable reducing agent, preferably sodiumcyanoborohydride, to give the isomeric compounds of Formulas IC1, IC2,IC3 and IC4. ##STR14##

Scheme VA

According to reaction scheme VA, an unsaturated nitrile of Formula 2 isreacted with a β-keto ester to afford a compound of Formula 24. Acompound of Formula 24 is then decarboxylated to afford a keto compoundof Formula 25. The ketone of Formula 25 is, in turn, treated with asuitable diol in the presence of a suitable acid catalyst, for example,ethylene glycol in the presence of p-toluenesulfonic acid, to afford aketal of Formula 26. The compound of Formula 26 is treated with asuitable reducing agent for reducing the cyano group to the amine toafford a compound of Formula 27. The cyano group is preferably reducedby catalytic hydrogenation, for example, over Raney nickel catalyst. Anamino compound of Formula 27 is then treated with a suitable reagent forforming separable diastereomeric carbamate derivatives of the amine, forexample a compound of Formula 27 is treated with BOC-anhydride to affordthe diastereomeric compounds of Formulas 28A (cis) and 28B (trans).##STR15##

Scheme VB

According to reaction scheme VB, the cis diastereomer of a compound ofFormula 28 (28A) is treated with a suitable acid, such astrifluoroacetic acid, for simultaneously cleaving the carbamate toafford the free amine and the ketal to form the ketone, which thencondense intramolecularly to afford a cyclic imine compound which is, inturn, reduced, preferably with sodium cyanoborohydride, to afford thediastereomeric compounds of Formulas 29 (the cis-anti isomer) and 31(the cis-syn isomer). The diastereomeric compounds of Formulas 29 and 31are separated, for example, by chromatography. The diastereomericcompounds of Formula 29A and Formula 29B are then treated with achloroformate derivative of an optically active alcohol, such as, forexample menthyl chloroformate (as shown in reaction scheme VB) oralternately, the chloroformate derivative of fenchol, borneol,α-naphthylethanol, myrtanol or nopol, to afford the separablediastereomeric carbamates of Formulas 30A and 30B. The chloroformatederivatives are readily prepared by treating the optically activealcohol with phosgene using standard procedures. The carbamates ofFormula 30 are separated and then treated with a suitable reducingagent, for example lithium aluminum hydride, to reduce the carbamate tothe N-methyl derivative affording the enantiomeric compounds of FormulasIC2 and IC3. The diastereomeric compounds of Formula 31 are treated inan identical manner to the compounds of Formula 29 to afford theenantiomeric compounds of Formulas IC1 and IC4. ##STR16##

Scheme VC

According to reaction scheme VC, the trans diastereomer of a compound ofFormula 28 (28B) is treated with a suitable acid, such astrifluoroacetic acid, for simultaneously cleaving the carbamate toafford the free amine and the ketal to form the ketone, which thencondense intramolecularly to afford a cyclic imine compound of Formula33. The imine is, in turn, reduced, preferably with sodiumcyanoborohydride, to afford the enantiomeric compounds of Formula 34(the trans-syn isomer). The compounds of Formula 34 are resolved asdescribed in reaction scheme VB by treatment with a chloroformatederivative of an optically active alcohol to afford the separablediastereomeric carbamates of Formulas 35A1 and 35B1. The carbamates ofFormula 30 are separated and then treated with a suitable reducingagent, for example, lithium aluminum hydride, to reduce the carbamate tothe N-methyl derivative affording the enantiomeric compounds of FormulasIC5 and IC6. ##STR17##

Scheme VI

According to reaction scheme VI, teralones of Formula 1 are condensedwith an acrylate ester, for example, ethyl acrylate, in the presence ofpyrrolidine and a suitable acid, such as p-toluenesulfonic acid, toafford the compounds of Formula 36. The compounds of Formula 36 areconverted to the compounds of Formula 37 by treatment with a suitablecyano derivative, for example, diethylcyanophosphonate, followed bytreatment with a suitable acid, for example p-toluenesulfonic acid inrefluxing toluene. The compounds of Formula 37 are cyclized to thelactams of Formula 38 by reduction of the cyano group to thecorresponding aminomethyl group which spontaneously condenses with theester group to form the lactam. The lactams of Formula 38 are convertedto the compounds of Formula VI as described in reaction scheme IV forthe conversion of the compounds of Formula 22 to the compounds ofFormula ID. ##STR18##

Scheme VII

According to reaction scheme VII, a racemic compound of Formula 38 istreated with a suitable base, such as, for example potassium t-butoxide,and benzyl bromide to give the N-protected compound, which is, in turn,treated with a Grignard reagent, as described previously in reactionscheme IV for the conversion of the compounds of Formula 22 to thecompound of Formula IV, to afford a racemic compound of Formula VI. Aracemic compound of Formula VI is then condensed with (-) menthylchloroformate to afford the diastereomeric carbamates of Formulas 40Aand 40B. The compounds of Formula 29 and 30 are treated with a suitablereducing agent, such as, for example, lithium aluminum hydride, toafford the optically active compounds of Formulas ID1 and ID2.

By "pharmaceutically acceptable" it is meant those salts which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio, effective for their intended use in thetreatment of depression and related mood and effective disorders. Thesalts can be prepared in situ during the final isolation andpurification of the compounds of Formula (I), or separately by reactingthe free base function with a suitable acid or cation. Representativeacid addition salts include hydrochloride, hydrobromide, sulfate,bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate,laurate, borate, benzoate, lactate, phosphate, toluenesulfonate,methanesulfonate, citrate, maleate, fumarate, succinate, tartrate,ascorbate, glucoheptonate, lactobionate, lauryl sulfate salts and thelike. Representative alkali or alkaline earth metal salts includesodium, calcium, potassium, magnesium salts and the like.

The term "affective disorder" as used herein refers to disorders thatare characterized by changes in mood as the primary clinicalmanifestation, cf, R. J. Baldessarini in Goodman and Gilman's ThePharmacological Basis of Therapeutics, A. G. Gilman, L. S. Goodman, T.W. Rall and F. Murad, Eds., Macmillan, New York, 1985, pp 412-432.

The term "biogenic amine uptake" as used herein refers to the selective,systems for attenuating and terminating the affects of the biogenicamines by actively transporting them into nerve terminals andsubsequently, into storage granules.

The term "depression" as used herein refers to "major depression" asdefined in the seventh edition of Goodman and Gilman's "ThePharmacological Basis of Therapeutics". Major depression isdistinguishable from normal grief, sadness and disappointment and ischaracterized by feelings of intense sadness and despair, mental showingand loss of concentration, pessimistic worry, agitation andself-deprecation. Physical changes also occur, including insomnia,anorexia and weight loss, decreased energy and libido, and disruption ofhormonal circadian rhythms.

Protocol for Uptake Inhibition Assays

The compounds of formula (I) inhibit the uptake of biogenic amineneurotransmitters into nerve terminals and, therefore, are useful intreatment of affective disorders. Such diseases include major depressionand the dipolar disorder, manic-depressive illness. The compounds ofthis invention may also be useful in the treatment of depressionassociated with other forms of mental illness, such as, for example,psychosis and dementia.

For the purpose of identifying compounds as biogenic amine uptakeinhibitors capable of interacting with the uptake carrier,ligand-carrier binding assays were carried out as an initial sceen. Theability of the compounds of the invention to interact with biogenicamine uptake carriers and to inhibit the neuronal uptake of biogenicamines can be demonstrated in vitro using the following protocols.

Synaptosomal Preparation

Male Sprague-Dawley derived rats, weighing about 180-250 g each(purchased from Sasco Animal Laboratories, Oregon, Wis.) were sacrificedby decapitation. The brains were immediately removed, placed on achilled glass plate and dissected according to a modification of themethod of Glowinski and Iversen (J. Glowinski and L. L. Iversen, JNeurochem, 1966, 13: 655-669). First, the rhombencephalon was separatedby a transverse section and discarded. The rest of the brain was dividedinto two portions by making another transverse section at the level ofthe optic chiasma. The hypothalamus, which was used for norepinephrineuptake studies, was removed from the posterior part by using theanterior commissure as the horizontal reference point and a line betweenthe posterior hypothalamus and mammillary bodies as the caudal limit.The striatum, which was used for dopamine uptake studies, was alsodissected from the posterior portion using the external wall of thelateral ventricle as the internal limit and the corpus collosum as theexternal limit. The frontal parts of the striatum were removed from theanterior portion of the cerebrum and combined with the striatal tissuefrom the posterior segment. The cortex, which was used for serotoninuptake studies, was composed of the rest of the anterior portion of thecerebrum and the cortical surfaces removed from the posterior segment.The hypothalamus and the striatum each weighed about 100 mg or slightlyless, whereas the cortex weighed up to 800 mg. The tissues were placedin a cold Potter-Elvehjem glass homogenizer with 5 (cortex) or 10(hypothalamus) or 20 (striatum) volumes of ice-cold 0.32M sucrose, pH 7,and homogenized by hand. The homogenate was centrifuged (on aMultifuge®, American Scientific Products) at 2500 rpm for 10 minutes ina refrigerated room (˜4° C.). The supernatant fraction containing thesynaptosomes was decanted, mixed thoroughly and kept on crushed ice foruse in the uptake studies.

Uptake Studies

Uptake studies were conducted according to the method of Snyder andCoyle (S. H. Snyder and J. T. Coyle, J Pharmacol Exp Ther, 1969, 165:78-86) with minor modifications. Usually a 0.1 mL aliquot of thesynaptosomal preparation was incubated in a mixture of 0.75 mL ofmodified Krebs-Ringer buffer, 0.05 mL of the drug being tested, and 0.1mL of a 1 μM solution of the labeled (tritiated) amine (finalconcentration 0.1 μM), for a total volume of 1 mL. The modifiedKrebs-Ringer bicarbonate buffer used in these studies contained 118 mMsodium chloride, 4 mM potassium chloride, 1.3 mM calcium chloride, 1.12mM potassium dihydrogen phosphate, 1.2 mM magnesium sulfate and 24 mMsodium bicarbonate, with the addition of 5 mM glucose, 0.15 mM disodiumEDTA, 12.5 μM nialamide and 1 mM ascorbic acid. Uptake was initiated bythe addition of the tritiated amine and the mixture was incubated at 37°C. in a Dubnoff Metabolic Shaking Incubator for 4 minutes. Apreincubation period was not included since it had been reported thatresults were similar with and without preincubation of the synaptosomalpreparation (G. Vosmer, et al. Biochem Pharmacol, 1980, 24: 2557-2562).Control incubations without the test drug were conducted at 37° C. todetermine total uptake and at 0° C. (in a crushed ice bath) to correctfor the diffusion of the tritiated amine into the synaptosomes and/orbinding.

Filtration was used to terminate uptake and collect the synaptosomes (C.A. Csernansky, et al. J Pharmacol Methods, 1985, 13: 187-191). In thefiltration technique, the incubation mixture was diluted with ice-cold0.9% aqueous sodium chloride solution and filtered through GF/B glassmicrofiber filters (Whatman) under reduced pressure. The filters weresubsequently washed four times with 5 mL of ice-cold 0.9% aqueous sodiumchloride solution and transferred to glass scintillation vials. Soluene(500 mL) and HIONIC FLUOR (Packard) scintillation fluid (3.5 mL) wereadded, and the vials were placed in a mechanical shaker forapproximately 1 hour. All the samples were cold- and dark-adapted andcounted in a Tri-Carb® (Packard) Model 460 Liquid ScintillationSpectrometer. Corrections were automatically made for quenching by theexternal standard method and for luminescence. All the results werebased on total radioactivity since it has been shown and is generallyaccepted that at least 85% of the synaptosomal content of the tritiatedamines was unmetabolized.

Uptake was calculated by subtracting the dpm (disintegrations perminute) in the 0° C. controls from the dpm in all other samples. Percentinhibition with the test drug was determined by comparison with thecontrols incubated at 37° C. IC₅₀ values, expressed as the molarconcentration of drug that inhibited uptake of the tritiated amine by50%, are shown in Table 2.

As used herein, the term "pharmaceutically acceptable carrier" means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxillary of any type. Someexamples of the materials that can serve as pharmaceutically acceptablecarriers are sugars, such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols such as glycerin, sorbitol, mannitoland polyethylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol and phosphate buffer solutions, as well as othernon-toxic compatible substances used in pharmaceutical formulations.Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfateand magnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents, andpreservatives can also be present in the composition, according to thejudgement of the formulator.

The compounds of the present invention may be administered alone or incombination or in concurrent therapy with other agents.

The specific therapeutically effective dose level for any particularpatient will depend upon a variety of factors including the disorderbeing treated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts.

The total daily dose of the compounds of this invention administered toa host in single or in divided doses can be in amounts, for example,from 0.01 to 25 mg/kg body weight or more usually from 0.1 to 15 mg/kgbody weight. Single dose compositions may contain such amounts orsubmultiples thereof to make up the daily dose. In general, treatmentregimens according to the present invention comprise administration to apatient in need of such treatment from about 10 mg to about 1000 mg ofthe compound(s) of this invention per day in multiple doses or in asingle dose of from 10 mg to 1000 mg.

This invention also provides pharmaceutical compositions in unit dosageforms, comprising a therapeutically effective amount of a compound (orcompounds) of this invention in combination with a conventionalpharmaceutical carrier.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,U.S.P. and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil can be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid are used in the preparation of injectables.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of a drug from subcutaneous or intramuscular injection.The most common way to accomplish this is to inject a suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug becomes dependent on the rate of dissolutionof the drug which is, in turn, dependent on the physical state of thedrug, for example, the crystal size and the crystalline form. Anotherapproach to delaying absorption of a drug is to administer the drug as asolution or suspension in oil. Injectable depot forms can also be madeby forming microcapsule matrices of drugs and biodegradable polymerssuch as polylactide-polyglycolide. Depending on the ratio of drug topolymer and the composition of the polymer, the rate of drug release canbe controlled. Examples of other biodegradable polymers includepoly-orthoesters and polyanhydrides. Depot injectables can also be madeby entrapping the drug in liposomes or microemulsions which arecompatible with body tissues.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycol which are solid at ordinary temperaturebut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, prills and granules. In such solid dosage formsthe active compound may be admixed with at least one inert diluent suchas sucrose, lactose or starch. Such dosage forms may also comprise, asis normal practice, additional substances other than inert diluents,e.g., tableting lubricants and other tableting aids such as magnesiumstearate and microcrystalline cellulose. In the case of capsules,tablets and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings andother release-controlling coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs containing inert diluents commonly used in the art such aswater. Such compositions may also comprise adjuvants, such as wettingagents; emulsifying and suspending agents; sweetening, flavoring andperfuming agents.

If desired, the compounds of the present invention can be incorporatedinto slow release or targeted delivery systems such as polymer matrices,liposomes and microspheres. They may be sterilized, for example, byfiltration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which candissolve in sterile water, or some other sterile injectable mediumimmediately before use.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above.

Dosage forms for topical or transdermal administration of a compound ofthis invention further include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulations, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispersing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

The foregoing may be better understood from the following examples,which are presented for the purpose of illustration and not intended tolimit the scope of the inventive concept.

EXAMPLE 1 cis/trans2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindolehydrochloride Step 1: 2-Phenylmethyl-1,3-dithiane

To a solution of 33.9 g (280 mmol) of phenylacetaldehyde and 35.6 g (330mmol) of 1,3-propanedithiol in 300 mL of methylene chloride at 0° C.,was added, dropwise over a period of 30 minutes, 10 mL of borontrifluoride etherate. The reaction mixture was allowed to warm toambient temperature and stirred for 3 h at ambient temperature. Thereaction mixture was made basic by the addition of 180 mL of 5% aqueouspotassium hydroxide solution and the resultant mixture was stirred for0.5 h. The layers were separated and the aqueous layer was extractedwith methylene chloride. The combined organic extract was washed with 1Naqueous sodium hydroxide solution and brine, dried over anhydrousmagnesium sulfate, filtered and the filtrate was distilled to afford53.62 g (91% yield) of the title compound, b.p. 150° C. (2 mm Hg); ¹ HNMR (CDCl₃) δ1.75-1.95 (1H, m), 2.05-2.17 (1H, m), 2.75-2.91 (4H, m),3.03 (2H, d, J=9 Hz), 4.25 (1H, t, J=9 Hz), 7.17-7.38 (5H, m).

Step 2: 1-Cyano-6-methoxy-3,4-dihydronaphthalene

Trimethylsilylcyanide (50.0 g, 510 mmol) was added to a suspension of75.0 g (430 mmol) of 6-methoxy-α-tetralone (commercially available fromAldrich Chemical Company) in 75 mL of anhydrous tetrahydrofuran (THF) atambient temperature. Lithium cyanide (100 mL of a 0.5M solution inN,N-dimethylformamide (DMF) was added to the resultant mixture in oneportion. The reaction mixture was stirred at ambient temperature for 1.5h and then the THF was removed under reduced pressure. The concentratewas partitioned between diethyl ether and water (5:1 v/v). The aqueouslayer was extracted with diethyl ether and the combined organic extractwas washed with brine, dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The residue was dissolved in400 mL of anhydrous toluene, containing 15 g of p-toluenesulfonic acid,previously refluxed in order to remove residual water by azeotropicdistillation. The mixture was heated at reflux (with a Dean Stark trap)for 1 h. The resultant solution was cooled to ambient temperature andwashed with cold 1N aqueous sodium hydroxide solution. The organic layerwas separated, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified on silica gel elutedwith 10% ethyl acetate in hexane to afford 48.09 g (60% yield) of thetitle compound. The physical properties of the product were identical tothe properties reported for this compound by F. Z. Basha, et al. in J.Organic Chemistry, 50: 4160-2 (1985).

Step 3:1-Cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene

To a solution of 14.0 g (66.7 mmol) of 2-phenylmethyl-1,3-dithiane (fromStep 1) in 250 mL of anhydrous THF at -20° C. under a nitrogenatmosphere was added 49 mL (73.4 mmol) of a 1.5M solution of n-butyllithium in hexane. The reaction mixture was stirred for approximately 1h at -20° C. and then was cooled to -78° C. A solution of 12 g (63.5mmol) of 1-cyano-6-methoxy-3,4-dihydronaphthalene, from Step 2, in 250mL of THF was added dropwise to the solution of2-benzyl-2-lithio-1,3-dithiane, and immediately the clear colorlesssolution become a reddish purple color. The reaction mixture was warmedto 0° C., was stirred at 0° C. for 1 h, and then was cooled to -78° C.and the reaction was quenched by the addition of 100 mL of saturatedaqueous ammonium chloride solution. Methylene chloride was added to thereaction mixture and the layers were separated. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The resultant oil was triturated with diethylether/hexane to afford 14.01 g (57% yield) of the cis isomer of thetitle compound. The material which was soluble in the diethylether/hexane was purified on silica gel eluted with 25% ethyl acetate inhexane to afford 9 g (36.6% yield) of a cis/trans mixture of the titlecompound; ¹ H NMR (CDCl₃) of cis isomer δ1.72-1.97 (2H, m), 2.02-2.18(1H, m), 2.45-2.97 (7H, m), 3.03-3.15 (1H, m) 3.1 , 3.72 (2H, dd J=15Hz), 3.78 (3H, s), 4.45 (1H, dd, J=4.6, 1.5 Hz), 6.69 (1H, d, J=3 Hz),6.78 (1H, dd, J=9 Hz, 3 Hz), 7.21 (1H, d, J=9 Hz), 7.25-7.45 (5H, m).

Step 4:1-Cyano-6-methoxy-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene

A mixture of 6.04 g (15.3 mmol) of the cis isomer of1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenefrom Step 3, 40 mL of ethylene glycol, 40 mL of THF and 17.0 g (45.8mmol) of mercury dichloride was stirred with a mechanical stirrer at 60°C. overnight. The mixture was filtered through Celite filter aid and thefilter cake was washed with methylene chloride. The THF was evaporatedand the residue was partitioned between water and methylene chloride(1:5, v/v). The aqueous layer was extracted twice with methylenechloride and discarded. The combined organic layers were washed twicewith water and once with brine, dried over anhydrous magnesium sulfate,filtered and concentrated. The residue was absorbed onto silica gel andpurified by flash chromatography on silica gel eluted with 25% ethylacetate in hexane to afford 3.69 g (69% yield) of the title compound; MSDCl--NH3 M/Z: 350 (M+H)⁺, 367 (M+NH4).sup. + ; ¹ H NMR (CDCl₃) δ2.0-2.18(3H, m), 2.68-2.83 (1H, m), 2.9-3.0 (1H, m), 2.95, 3.1 (2H, dd, J=15Hz), 3.62-3.7 (1H, m), 3.72 (3H, s), 3.84-3.92 (1H, m), 4.02-4.13 (3H,m), 6.62 (1H, d, J=3.0 Hz), 6.72 (1H, dd, J=9.0 Hz, 3.0 Hz), 7.1 (1H, d,J=9.0 Hz), 7.2-7.3 (5H, m).

Step 5:1-Aminomethyl-6-methoxy-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene

1-Cyano-6-methoxy-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene(3.7 g, 10.6 mmol) from Step 4 was dissolved in 135 mL of methanol and15 mL of condensed ammonia and the resultant solution was treated for 24h at ambient temperature with hydrogen gas (4 atmospheres) in thepresence of 7.4 g of Raney nickel #28 catalyst. The hydrogenationmixture was filtered and concentrated in vacuo. The residue was absorbedonto silica gel and purified on silica gel eluted with ethylacetate:formic acid:water (8:1:1, v/v/v) to give the formic acid salt ofthe desired product which was dissolved in water. The aqueous solutionwas made basic by the addition of sodium hydroxide and then extractedwith methylene chloride. The organic phase was concentrated underreduced pressure to afford 3.15 g (84% yield) of the title compound: MSDCl--NH₃ M/Z: 354 (M+H)⁺, 371 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ1.53-1.7 (1H,m), 2.07-2.2 (2H, m), 2.52-2.87 (5H, m), 2.86, 2.97 (2H, dd, J=15 Hz),3.30-3.50 (2H, m), 3.62-3.72 (1H, m), 3.75 (3H, s), 3.84-3.92 (1H, m),6.67 (1H, d, J=3.0 Hz), 6.74 (1H, dd, J=9.0 Hz, 3.0 Hz), 7.17 (1H, d,J=9.0 Hz), 7.2-7.3 (5H, m).

Alternately, the title compound was purified by conversion to thecorresponding hydrochloride salt by treatment of the residue from thehydrogenation reaction with methanol saturated with anhydrous hydrogenchloride. In one preparation, the hydrochloride salt of the titlecompound was recrystallized from diethyl ether/ethyl alcohol to affordthe hydrochloride salt of the title compound in 78% yield.

Step 6: cis/trans2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindolehydrochloride

A solution of 3.15 g (8.21 mmol) of1-aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl[-6-methoxy-1,2,3,4-tetrahydronaphthalene,from Step 5, in 120 mL of THF and 60 mL of 3N aqueous hydrochloric acidsolution was stirred overnight at ambient temperature. The reactionmixture was evaporated to near dryness and the residual oil wasdissolved in 200 mL of methanol. To the methanol solution was added afew crystals of bromocresol green indicator, followed by 7 g of sodiumcyanoborohydride. After 15 minutes, the solvent was evaporated and theresidue was partitioned between methylene chloride and water (4/1, v/v).The layers were separated and the aqueous layer was extracted twice withmethylene chloride. The combined organic layers were concentrated andthe concentrated solution adsorbed onto silica gel. The silica gel wasloaded onto a silica gel column and elution with ethyl acetate:formicacid:water (18:1:1, v/v/v) to afford 2.50 g (94% yield) of the formicacid salt of title compound as a 7/3 cis/trans mixture at the ringjuncture. The free amine was prepared by dissolving the formic acid saltin water, adding sodium hydroxide to make the solution basic andextracting the basic solution with methylene chloride. The methylenechloride was removed under reduced pressure and the residue wasdissolved in diethyl ether saturated with anhydrous hydrogen chloride.The desired hydrochloride salt was collected by filtration, m.p.238-239; MS DCl--NH₃ M/Z: 294 (M+H)⁺ ; ¹ H NMR (CDCl₃) mixture of cis:δ1.46-1.62 (1H, m), 1.83-1.95 (1H, m), 2.16-2.28 (1H, m), 2.63-2.97 (5H,m), 3.27-3.47 (2H, m), 3.59-3.69 (1H, m), 3.77 (3H, s), 6.67 (1H, d,J=3.0 Hz), 6.7 (1H, dd, J=9.0 Hz, 3.0 Hz), 6.97 (1H, d, J=9.0 Hz),7.17-7.36 (5H, m). trans: δ1.42-1.62 (2H, m), 1.8-1.9 (2H, m), 2.63-2.97(5H, m), 3.14-3.25 (1H, m), 3.47-3.57 (1H, m), 3.77 (3H, s), 6.69 (1H,d, J= 3.0 Hz), 6.87 (1H, d, J=9.0 Hz), 7.0 (1H, dd, J=9.0 Hz, 3.0 Hz),7.17-7.36 (5H, m). Analysis calculated for C₂₀ H₂₄ ClNO+0.5H₂ O: C,70.89; H, 7.44; N, 4.13. Found: C, 70.43; H, 7.19; N, 4.08.

EXAMPLE 2cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

A solution of 1.18 g (4.0 mmol) of2,3,3a,4,5,9b-hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindole(the product of Example 1) and 2.07 mL of formalin (37% aqueousformaldehyde solution) in 100 mL of methanol was hydrogenated at ambienttemperature with 4 atmospheres of hydrogen for 24 h in the presence of0.24 g of 20% palladium on carbon. The hydrogenation mixture wasfiltered and the filtrate was concentrated in vacuo. The residue wasadsorbed on silica gel and chromatographed on silica gel eluted withdiethyl ether:hexane presaturated with ammonia (7:2, v/v) to give 690 mg(56% yield) of the amine product which was converted to the titlecompound by treatment with 1.1 equivalents of methanesulfonic acid inacetone/diethyl ether solution, m.p. 149.5°-150.3° C.; MS DCl--NH₃ M/Z:308 (M+H)⁺ ; ¹ H NMR of the methanesulfonic acid salt (CDCl₃) δ1.8-2.1(2H, m), 2.45- 2.57 (1H, m), 2.6-2.78 (2H, m), 2.85-2.97 (1H, m), 2.79(3H, s), 2.83 (3H, d, J=6 Hz), 3.2-3.4 (2H, m), 3.5-3.7 (2H, m), 3.77(3H, s), 3.9-4.02 (1H, m), 6.65 (1H, d, J=3 Hz), 6.7 (1H, dd, J=9 Hz, 3Hz), 6.88 (1H, d, J=9 Hz), 7.28-7.43 (5H, m). Analysis calculated forC₂₂ H₂₉ NO₄ S: C, 65.48; H, 7.24; N, 3.47. Found: C, 65.53; H, 7.20; N,3.42.

EXAMPLE 3cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonate salt

2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindole(0.97 g, 3.2 mmol), the product of Example 1, was dissolved in 10 mL ofpyridine and approximately 10 mL of acetic anhydride was added to theresultant solution. The reaction mixture was stirred at ambienttemperature for 0.5 h and then most of the pyridine was removed invacuo. The concentrate was partitioned between ethyl acetate and diluteaqueous hydrochloric acid solution (4:1 v/v) and the layers wereseparated. The aqueous layer was extracted twice with ethyl acetate andthe combined organic layers were washed with dilute aqueous sodiumhydroxide solution, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The residue was dissolved in 20 mL of anhydrousTHF and borane-THF complex (15 mL of a 1.0M solution in THF, 15 mmol)was added to the resultant solution. The reaction mixture was heated atreflux for 1 h. The THF was removed in vacuo and the residue wasdissolved in 20 mL of methanol saturated with anhydrous hydrogenchloride. The solution was heated at reflux overnight and the solventwas removed in vacuo. The residue was partitioned between methylenechloride and 15% aqueous potassium hydroxide solution (4:1 v/v) and thelayers were separated. The aqueous layer was extracted with two portionsof methylene chloride and the combined organic layers were dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified on silica gel eluted with a 2:1 mixture of hexanesand diethyl ether saturated with ammonia to give 840 mg (˜85% yield) ofthe product as the free amine. The amine product was dissolved in asolution of methanesulfonic acid in diethyl ether to give the titlecompound, m.p. 166.0°-167.1° C.; MS DCl--NH₃ M/Z: 322 (M+H)⁺. Analysiscalculated for C₂₃ H₃₁ NO₄ S: C, 66.16; H, 7.48; N, 3.35. Found: C,65.79; H, 7.44; N, 3.38.

EXAMPLE 4cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-phenylethyl-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindole(0.80 g, 2.73 mmol), the product of Example 1, was dissolved in 10 mL ofmethylene chloride and approximately 5 mL of pyridine was added to theresultant solution. The solution was cooled to 0° C. and approximately2.5 mL of phenylacetyl chloride was added, dropwise, over a 3 minuteperiod and the reaction mixture was stirred for 45 minutes at ambienttemperature. Water (20 mL) was added to the reaction mixture to quenchthe reaction and the resultant mixture was stirred at ambienttemperature for 0.5 h. the mixture was transferred to a separatoryfunnel and 1N aqueous hydrochloric acid solution and 4 mL of methylenechloride were added. The layers were separated and the aqueous layer wasextracted with two portions of methylene chloride. The combined organiclayers were washed with 1N aqueous hydrochloric acid solution and 1Ndilute aqueous sodium hydroxide solution, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified onsilica gel eluted with hexane:ethyl acetate (5:2 v/v) to give theintermediate amide,2,3,3a,4,5,9b-hexahydro-7-methoxy-2-phenylmethylcarbonyl-3-phenylmethyl-1H-benz[e]isoindole,which was dissolved in 10 mL of anhydrous THF. Borane (4 mL of a 1.0Msolution in THF, 4 mmol) was added to the solution of the amide and thereaction mixture was heated at reflux for 1 h. The solvent was removedin vacuo and the residue was dissolved in methanol. Methanol saturatedwith anhydrous hydrogen chloride was added and the solution was heatedat reflux for 16 h. The methanol was removed under reduced pressure andthe residue was partitioned between 1N aqueous sodium hydroxide solutionand methylene chloride (1:4, v/v). The aqueous layer was extracted withtwo portions of methylene chloride and the combined organic layers weredried over anhydrous magnesium sulfate and filtered. Silica gel wassuspended in the filtrate and the solvent was evaporated from thesuspension to give a powder which was loaded onto a silica gel column.The column was eluted with a 5:1 mixture of hexane and diethyl ethersaturated with ammonia to give 530 mg (49% yield) of the free amineproduct. The methanesulfonate salt (the title compound) was formed bydissolving the free amine product in a diethyl ether solution ofmethanesulfonic acid, m.p. 179°-180° C.; MS DCl--NH₃ M/Z: 398 (M+H)⁺ ; ¹H NMR of methanesulfonic acid salt (CDCl₃) δ1.94-2.1 (2H, m), 2.4-2.77(2H, m), 2.83 (3H, s), 2.83-3.1 (3H, m), 3.2-3.55 (6H, m), 3.7-3.8 (1H,m), 3.78 (3H, s), 3.83, 3.93 (1H, dd, J=15 Hz, 9 Hz), 6.64 (1H, d, J=3Hz), 6.69 (1H, dd, J=3 Hz, J=9 Hz), 6.89 (1H, d, J=9 Hz), 7.07-7.42(10H, m). Analysis calculated for C₂₉ H₃₅ NO₄ S: C, 70.56; H, 7.15; N,2.84. Found: C, 70.19; H, 7.19; N, 2.80.

EXAMPLE 5cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-(3-chlorophenyl)ethyl-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindole(0.50 g, 1.7 mmol), the product of Example 1, 1-hydroxybenzotriazole(0.276 g, 2.04 mmol), and 3-chlorophenylacetic acid (0.35 g, 2.04 mmol),commercially available from Aldrich Chemical Company, were dissolved in5 mL of dry THF under a nitrogen atmosphere. Dicyclohexylcarbodiimide(0.422 g, 2.04 mmol) was added dropwise to the resultant solution. Thereaction mixture was stirred at ambient temperature under a nitrogenatmosphere for 48 h. The reaction mixture was then filtered and thefiltrate was concentrated in vacuo. The solid residue was dissolved inethyl acetate and the ethyl acetate solution was washed with 1N aqueoushydrochloric acid solution and 1N aqueous sodium hydroxide solution,dried over anhydrous magnesium sulfate, filtered and concentrated invacuo. The residue was dissolved in 20 mL of anhydrous THF and borane(3.5 mL of a 1.0M solution in THF, 3.5 mmol) was added to the resultantsolution. The reaction mixture was heated at reflux under a nitrogenatmosphere for 2 h. Methanol saturated with anhydrous hydrogen chloridewas added and the reaction mixture was heated at reflux for 3 h and thenstirred at ambient temperature overnight. The solvents were evaporatedin vacuo and the residue was made basic with 1N aqueous sodium hydroxidesolution. The aqueous solution was extracted with three portions ofmethylene chloride and the combined methylene chloride layers were driedover anhydrous magnesium chloride, filtered and concentrated in vacuo toafford ˜310 mg (42% yield) of the free base. The residue was dissolvedin an diethyl ether solution of methanesulfonic acid and the solutionwas concentrated to give the title compound, m.p. 195°-196° C.; MSDCl--NH₃ M/Z: 432 (M+H)⁺ ; .sup. 1 H NMR of methanesulfonic acid salt(CDCl₃) δ1.92-2.1 (2H, m), 2.45-2.75 (2H, m), 2.82 (3H, s), 2.82-3.04(3H, m), 3.07-3.57 (6H, m), 3.67-3.96 (2H, m), 3.74 (3H, s), 6.63 (1H,d, J=3 Hz), 6.68 (1H, dd, J=3 Hz, 9 Hz), 6.92 (1H, d, J=9 Hz), 6.97-7.45(9H, m). Analysis calculated for C₂₉ H₃₄ NClO₄ S: C, 65.96; H, 6.49; N,2.65. Found: C, 65.45; H, 6.50; N, 2.62.

EXAMPLE 6trans-2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt Step 1:1-Cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalene

A mixture of 7.40 g (18.7 mmol) of1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 3 of Example 1), 15.2 g (56 mmol) of mercuricchloride and 7.5 g (74.8 mmol) of calcium carbonate in 190 mL of 80%aqueous acetonitrile solution was heated at reflux temperature overnightwhile being stirred with a mechanical stirrer, and was then cooled in anice/water bath. To the cooled reaction mixture was added approximately50 mL of concentrated sodium sulfide (Na₂ S) and the resultant mixturewas stirred with a mechanical stirrer for 10 minutes at 0° C. Themixture was filtered through Celite filter aid and the filtrate wasconcentrated in vacuo. The residue was partitioned between water andmethylene chloride (1:4, v/v) and the resultant emulsion was filteredthrough Celite filter aid. The layers of the filtrate were separated andthe aqueous layer was extracted with three portions of methylenechloride. The organic layers were combined, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified on silica gel eluted with 3:1 hexane:ethyl acetate, followed by2:1 hexane:ethyl acetate to give 4.29 g (75% yield) of the titlecompound, m.p. 139°-142° C.; MS DCl--NH₃ M/Z: 323 (M+NH₄)⁺ ; ¹ H NMR cisisomer (CDCl₃) δ1.66-1.72 (1H, m), 2.11-2.22 (1H, m), 2.66-2.89 (2H, m),3.16-3.26 (1H, m), 3.76 (3H, s), 3.90 (2H, d), 4.29 (1H, d), 6.60 (1H,d, J=3 Hz), 6.78 (1H, dd, J=3 Hz, 9 Hz), 7.21-7.40 (6H, m); ¹ H NMRtrans isomer (CDCl₃) δ2.04-2.22 (1H, m), 2.26-2.38 (1H, m), 2.73-2.98(3H, m), 3.75 (3H, s), 3.87 (2H, s), 4.09 (1H, d), 6.62 (1H, d, J=3 Hz),6.77 (1H, dd, J=9 Hz, 3 Hz), 7.15 (1H, d, J= 9 Hz), 7.19-7.39 (5H, m).

Step 2:trans-2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

A solution of 3.05 g (10 mmol) of1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalene,from Step 1, in 200 mL of methanol containing 30 mL of triethylamine washydrogenated (4 atmospheres of H₂), at ambient temperature, in thepresence of 12.09 g of Raney nickel #28. The reaction mixture wasfiltered and the filtrate concentrated under reduced pressure. Theresidue was purified on silica gel eluted with ethyl acetate:formicacid:water (19:0.5:0.5 v/v/v) to give 2.61 g (90% yield) of the titlecompound; MS DCl--NH₃ M/Z: 294 (M+H)⁺ ; ¹ H NMR of trans isomer (CDCl₃)δ1.33-1.52 (2H, m), 1.74-1.89 (1H, m), 1.92 (1H, bs), 2.72 (3H, s),2.77-2.86 (2H, m), 2.98-3.10 (2H, m), 3.22-3.36 (1H, m), 3.39-3.48 (1H,m), 3.61-3.74 (1H, m), 3.77 (3H, s), 3.91-4.02 (1H, m), 6.64 (1H, d, J=3Hz), 6.68 (1H, dd, J=3 Hz, 9 Hz), 6.82 (1H, d, J=9 Hz), 7.21-7.40 (5H,m), 8.93 (1H, bs), 9.51 (1H, bs). Analysis calculated for C₂₁ H₂₅ NO₃ :C, 64.76; H, 3.60; N, 6.99. Found: C, 64.58; H, 3.54; N, 6.71.

EXAMPLE 7trans-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindole

Following the procedures described in Example 2, substituting theproduct of Example 6 for the product of Example 1, the title compoundwas prepared, m.p. 168.5°-169° C.; MS DCl--NH₃ M/Z: 308 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ1.19-1.37 (1H, m), 1.45-1.58 (1H, m), 1.75-1.95 (1H, m),1.95-2.17 (1H, m), 2.67 (3H, s), 2.79-3.00 (2H, m), 3.00-3.18 (2H, m),3.18-3.47 (2H, m), 3.55-3.72 (1H, m), 3.77 (3H, s), 4.02-4.19 (1H, m),6.65-6.72 (2H, m), 6.78 (1H, d), 7.29 (1H, t), 7.36 (2H, d), 7.47 (2H,d). Analysis calculated for C₂₁ H₂₅ NO: C, 65.48; H, 3.47; N, 7.18.Found: C, 65.54; H, 3.42; N, 7.30.

EXAMPLE 8cis-anti-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Examples 1 and 2 on a largerscale, a minor product was obtained from the final purification whichwas identified as the title compound, m.p. 140.5°-141.0° C.; MS DCl--NH₃M/Z: 308 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.30-1.43 (1H, m), 1.51-1.62 (1H, m),2.53-2.61 (1H, m), 2.62-2.79 (2H, m), 2.73 and 2.76 (2 singlets in a 1:1ratio, N--CH₃), 2.90 (3H, s), 3.04-3.15 (1H, m), 3.18-3.27 (1H, m),3.42-3.50 (1H, m), 3.77 (3H, s), 3.88-3.98 (1H, m), 4.28-4.37 (1H, m),6.62 (1H, d, J=3 Hz), 6.74 (1H, dd, J=3 Hz, 9 Hz), 7.08 (1H, d, J=9 Hz),7.25-7.41 (5H, m). Analysis calculated for C₂₂ H₂₉ NO₄ S: C, 65.48; H,7.24; N, 3.47. Found: C, 65.27; H, 7.29; N, 3.46.

EXAMPLE 9cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt Step 1: 1-Cyano-3,4-dihydronaphthalene

Following the procedures described in Step 2 of Example 1, replacing6-methoxy-α-tetralone with α-tetralone (commercially available fromAldrich Chemical Company), the title compound was prepared. The physicalproperties of the product were identical to those reported for thiscompound by F. Z. Basha, et al. in J Organic Chemistry, 50: 4160-2(1985).

Step 2;1-Cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 3 of Example 1 for theconjugate addition of 2-benzyl-1,3-dithiane (14.2 g, 67 mmol), replacing1-cyano-6-methoxy-3,4-dihydronaphthalene with 10 g (64.4 mmol) of1-cyano-3,4-dihydronaphthalene (the product of Step 1 of this Example),the title compound was prepared in 77% yield (18.25 g); MS DCl--NH3 M/Z:366 (M+H)⁺.

Step 3:1-Cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures of Step 4 of Example 1, replacing1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene,from Step 2 above, the title compound was prepared; MS DCl--NH₃ M/Z: 320(M+H)⁺, 337 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ2.07-2.25 (3H, m), 2.75-2.9 (1H,m), 2.94-3.1 (1H, m), 2.97-3.13 (2H, dd, J=15 Hz), 3.65-3.75 (1H, m),3.87-3.98 (1H, m), 4.08-4.19 (3H, m), 7.1-7.3 (9H, m).

Step 4:1-Aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 5 of Example 1, replacing1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene,from Step 3 above, the title compound was prepared in 55% yield; MSDCl--NH₃ M/Z: 324 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.4-1.6 (1H, m), 2.02-2.2(2H, m), 2.5-3.0 (5H, m), 2.84, 2.95 (2H, dd, J=15 Hz), 3.34-3.47 (2H,m), 3.6-3.7 (1H, m), 3.8-3.9 (1H, m), 7.05-7.34 (9H, m).

Step 5: 2,3,3a,4,5,9b-Hexahydro-3-phenylmethyl-1H-benz[e]isoindole

Following the procedures described in Step 6 of Example 1, replacing1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene,from Step 4 above, the title compound was prepared in 77% yield (3.15 g)as a mixture of unseparable diastereomers; MS DCl--NH₃ M/Z: 263 (M+H)⁺ ;¹ H NMR of the free base (CDCl₃) δ1.45-1.64 (2H, m), 1.85-1.95 (1H, m),2.5-3.0 (5H, m), 3.3-3.65 (3H, m), 6.9-7.4 (9H, m).

Step 6:cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Example 2, replacing the productof Example 1 with the product of Step 5 of this Example,2,3,3a,4,5,9b-hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindole wasprepared as a mixtures of diastereomers which were separated bychromatography on silica gel eluted with 2:1 hexane: diethyl ether(saturated with ammonia) to give 780 mg of the title compound (the lesspolar diastereomer) in 28% yield, m.p. 168.2°-169.2° C.; MS DCl--NH₃M/Z: (M+H)⁺ 278; ¹ H NMR of the free base (CDCl₃) δ1.57-1.75 (1H, m),1.9-2.02 (1H, m), 2.1-2.24 (1H, m), 2.4 (3H, s), 2.5-2.65 (1H, m),2.7-2.82 (2H, m), 2.87 (3H, m), 3.17-3.24 (1H, m), 3.29-3.37 (1H, m),7.0-7.35 (9H, m). Analysis calculated for C₂₁ H₂₇ NO₃ S: C, 67.53; H,7.28; N, 3.75. Found: C, 67.51; H, 7.36; N, 3.72.

EXAMPLE 10trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

From Step 6 of Example 9, the title compound (the more polardiastereomer) was obtained, after chromatography, in 56% yield; MSDCl--NH₃ M/Z: 278 (M+H)⁺ ; ¹ H NMR of methanesulfonic acid salt (CDCl₃)δ1.45-1.6 (1H, m), 1.75-1.86 (1H, m), 2.04-2.19 (1H, m), 2.3-2.4 (1H,bs), 2.77 (3H, d, J=6 Hz), 2.84 (3H, s), 3.86-3.97 (2H, m), 3.1-3.27(3H, m), 3.4-3.57 (2H, m), 4.03-4.15 (1H, m), 6.85 (1H, d, J=9 Hz),7.1-7.43 (8H, m). Analysis calculated for C₂₁ H₂₇ NO₃ S: C, 67.53; H,7.28; N, 3.75. Found: C, 67.27; H, 7.29; N, 3.72.

EXAMPLE 11cis-2,3,3a,4,5,9b-Hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindolehydrochloride Step 1: 2-(3-Methylphenyl)methyl-1,3-dithiane

Following the procedures described in Step 1 of Example 1, replacingphenylacetaldehyde with 3-methyl-phenylacetaldehyde the title compoundwas prepared; MS DCl--NH₃ M/Z: 221 (M+H)⁺.

Step 2:1-Cyano-2-[1-(1,3-dithiane)-2-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 3 of Example 1, replacing1-cyano-6-methoxy-3,4-dihydronaphthalene with 11.63 g (74.9 mmol) of1-cyano-3,4-dihydronaphthalene (the product of Step 1 of Example 9) and2-phenylmethyl-1,3-dithiane with 16.5 g (75 mmol) of2-(3-methylphenyl)methyl-1,3-dithiane (the product of Step 1 of thisExample), the title compound was prepared in 65% yield (18.5 g), m.p.125°-128° C.; MS DCl--NH₃ M/Z: 380 (M+H)⁺ ; ¹ H NMR of cis isomer(CDCl₃) δ1.72-2.0 (2H, m), 2.07-2.2 (1H, m), 2.35 (3H, s), 2.48-3.02(7H, m), 3.67, 3.72 (2H, dd, J=15 Hz), 3.12-3.27 (1H, m), 4.48 (1H, dd,J=4.6 Hz, 1.5 Hz), 7.04- 7.33 (8H, m).

Step 3:1-Cyano-2-[1-(1,3-dioxolane)-2-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures of Step 4 of Example 1, replacing1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 16 g (42 mmol) of1-cyano-2-[1-(1,3-dithiane)-2-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of this Example), the title compound was preparedin 60% yield (8.5 g); MS DCl--NH₃ M/Z: 334 (M+H)⁺, (M+NH₄)⁺ 351; ¹ H NMR(CDCl₃) δ2.04-2.23 (3H, m), 2.33 (3H, s), 2.7-2.9 (1H, m), 2.92-3.05(1H, m), 2.93, 3.07 (2H, dd, J=15 Hz), 3.71-3.81 (1H, m), 3.92-4.02 (1H,m), 4.08-4.18 (3H, m), 7.02-7.28 (8H, m).

Step 4:1-Aminomethyl-2-[1-(1,3-dioxolane)-2-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures of Step 5 of Example 1, replacing1-cyano-2-[1-(1,3-dioxolane)-2-(3-methylphenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 8.5 g (25.5 mmol) of1-cyano-2-[1-(1,3-dioxolane)-2-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydronaphthalene(the product of Step 3 of this Example), the title compound was prepared93% yield (8 g); MS DCl--NH₃ M/Z: 338 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.54-1.7(1H, m), 2.07-2.22 (2H, m), 3.02 (3H, s), 2.54-3.0 (5H, m), 2.83-2.93(2H, dd, J=18.0 Hz), 3.3-3.52 (2H, m), 3.65-3.72 (1H, m), 3.82-3.9 (1H,m), 6.97-7.22 (8H, m).

Step 5:cis-2,3,3a,4,5,9b-Hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindolehydrochloride

Following the procedures of Step 6 of Example 1, replacing1-aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-7-methoxy-1,2,3,4-tetrahydronaphthalenewith1-aminomethyl-2-[1-(1,3-dioxolane)-2-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydronaphthalene(the product of Step 4 of this Example), the title compound was preparedin 70% yield (5 g), m.p. 220°-222° C.; MS DCl--NH₃ M/Z: 278 (M+H)⁺.Analysis calculated for C₂₀ H₂₄ ClN: C, 76.53; H, 7.71; N, 4.46. Found:C, 76.29; H, 7.75; N, 4.45.

EXAMPLE 12cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 2, replacing the productof Example 1 with 2.13 g (7.7 mmol) of the product of Example 11, thecis isomer of the title compound was prepared in 52% yield (1.16 g),m.p. 208°-210° C.; MS DCl--NH₃ M/Z: 292 (M+H)⁺ ; ¹ H NMR of free amine(CDCl₃) δ1.57-1.73 (1H, m), 1.93-2.03 (1H, m), 2.13-2.25 (1H, m), 2.35(3H, s), 3.4 (3H, s), 2.5-2.97 (6H, m), 3.15-3.23 (1H, m), 3.26-3.75(1H, m), 7.0-7.26 (8H, m). Analysis calculated for C₂₁ H₂₆ ClN+1/4 H₂ O:C, 75.88; H, 8.09; N, 4.21. Found: C, 75.82; H, 8.00; N, 4.33.

EXAMPLE 13 cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 3, replacing the productof Example 1 with 1.1 g (3.97 mmol) of the product of Example 11, thetitle compound was prepared in 75% yield (0.82 g), m.p. 250°-252° C.; MSDCl--NH₃ M/Z: 306 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.03-1.18 (3H, t, J=7.5 Hz),1.6-2.5 (5H, m), 2.13-2.23 (1H, m), 2.35 (3H, s), 2.5-3.0 (5H, m),3.03-3.15 (1H, m), 3.2-3.33 (1H, m), 7.0-7.22 (8H, m). Analysiscalculated for C₂₂ H₂₈ ClN: C, 76.26; H, 8.29; N, 4.04. Found: C, 75.98;H, 8.11; N, 3.86.

EXAMPLE 14trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-1H-benz[e]isoindolemethanesulfonic acid salt Step 1:1-Cyano-2-(3-methylphenyl)methylcarbonyl-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 1 of Example 6, replacing1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 2.35 g (6.2 mmol) of1-cyano-2-[1-(1,3-dithiane)-2-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of Example 11) the title compound was prepared in67% yield (1.2 g) as a 2:1 mixture of the cis and trans isomers; MSDCl--NH₃ M/Z: 290 (M+H)⁺.

Step 2:2,3,3a,4,5,9b-Hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindole

Following the procedures described in Step 2 of Example 6, replacing1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalene(the product of Step 1 of Example 6) with the product of Step 1 above,1-cyano-2-(3-methylphenyl)methylcarbonyl-1,2,3,4-tetrahydronaphthalene,the title compound was prepared; MS DCl--NH₃ M/Z: 278 (M+H)⁺.

Step 3:trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Example 7, replacing the productof Example 6 with the product of Step 2 of this Example, the titlecompound was prepared, m.p. 128°-130° C.; MS DCl--NH₃ M/Z: 292 (M+H)⁺ ;¹ H NMR (CDCl₃) δ1.45-1.6 (1H, m), 1.73-1.87 (1H, m), 2.02-2.2 (1H, m),2.37 (3H, s), 2.77 (3H, d, J=6 Hz), 2.85 (3H, s), 2.9-3.3 (2H, m),3.05-3.23 (3H, m), 3.35-3.45 (1H, m), 3.53-3.63 (1H, m), 4.03-4.18 (1H,m), 6.88-6.92 (1H, d, J=9 Hz), 7.07-7.3 (7H, m). Analysis calculated forC₂₂ H₂₉ NO₃ S+H₂ O: C, 65.16; H, 7.70; N, 3.45. Found: C, 64.73; H,7.23; N, 3.39.

EXAMPLE 15cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindolehydrochloride Step 1: 2-(3-Fluorophenyl)methyl-1,3-dithiane

1,3-Dithiane (12 g, 0.1 mol) was dissolved in 150 mL of anhydrous THFunder a nitrogen atmosphere. The resultant solution was cooled to -78°C. and n-butyllithium (44 mL of a 2.5M solution of in hexane, 0.11 mol)was added. The reaction mixture was warmed to -23° C. and then stirredat -23° C. for 0.5 h. The reaction mixture was recooled to -78° C. and25 g (0.135 mol) of 3-fluorobenzyl bromide was added over a 15 minuteperiod. The reaction mixture was stirred for 3 h at ambient temperatureand then diluted with methylene chloride, washed with aqueous ammoniumchloride solution and brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The residue wasdistilled to afford 15.2 g (66.7% yield) of the title compound, b.p.135°-140° C. (0.5 mm Hg); MS DCl--NH₃ M/Z: 229 (M+ H)⁺ ; ¹ H NMR (CDCl₃)δ1.77-1.95 (1H, m), 2.05-2.18 (1H, m), 2.8-2.9 (4H, m), 3.02 (2H, d,J=7.5 Hz), 4.23 (1H, t, J=7.5 Hz), 6.9-7.1 (3H, m), 7.23-7.33 (1H, m).

Step 2:1-Cyano-2-[1-(13-dithiane)-2-(3-fluorophenyl)ethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 3 of Example 1, replacing1-cyano-6-methoxy-3,4-dihydronaphthalene with 8.37 g (54 mmol) of1-cyano-3,4-dihydronaphthalene (the product of Step 1 of Example 9) and2-phenylmethyl-1,3-dithiane with 13.68 g (60 mmol) of2-(3-fluorophenyl)methyl-1,3-dithiane (the product of Step 1 of thisExample), the title compound was prepared in 45% yield (10.4 g); MSDCl--NH₃ M/Z: 384 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.72-2.20 (3H, m), 2.48-3.0(7H, m), 3.1-3.2 (1H, m), 3.07, 3.75 (2H, dd, J=15 Hz), 4.5 (1H, dd,J=4.6 Hz, 1.5 Hz), 6.94-7.03 (1H, m), 7.14-7.34 (7H, m).

Step 3:1-Cyano-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 4 of Example 1, replacing1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 10.4 g (27 mmol) of1-cyano-2-[1-(13-dithiane)-2-(3-fluorophenyl)ethyl]-1,2,3,4-tetrahydronaphthalene,from Step 2 of this Example, the title compound was prepared in 52%yield (4.7 g); MS DCl--NH₃ M/Z: 338 (M+H)⁺.

Step 4:1-Aminomethyl-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 5 of Example 1, replacing1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 4.7 g (14 mmol) of1-cyano-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-1,2,3,4-tetrahydronaphthalene,from Step 3 of this Example, the title compound was prepared in 86%yield (4.1 g); MS DCl--NH₃ M/Z: 342 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.5-1.7(1H, m), 2.07-2.23 (2H, m), 2.57-3.04 (5H, m), 2.85, 3.02 (2H, dd, J=15Hz), 3.37-3.53 (2H, m), 3.67-3.74 (1H, m), 3.82-3.91 (1H, m), 6.88-7.3(8H, m).

Step 5:cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindolehydrochloride

Following the procedures described in Step 6 of Example 1, replacing1-aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 4.1 g (12 mmol) of1-aminomethyl-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-1,2,3,4-tetrahydronaphthalene,from Step 4 of this Example, the title compound was prepared in 33%yield (1.3 g), m.p. 255°-258° C.; MS DCl--NH₃ M/Z: 282 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ1.45-1.63 (1H, m), 1.83-1.95 (1H, m), 2.2-2.33 (1H, m),2.53-3.0 (5H, m), 3.33-3.53 (2H, m), 3.0-3.68 (1H, m), 6.85-7.2 (7H, m),7.2-7.32 (1H, m). Analysis calculated for C₂₀ H₂₁ ClFN: C, 71.80; H,6.66; N, 4.41. Found: C, 71.65; H, 6.68; N, 4.41.

EXAMPLE 16cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 2, replacing the productof Example 1 with the product of Example 15, the title compound wasprepared in 65% yield (0.8 g), m.p. 208°-210° C.; MS DCl--NH₃ M/Z: 296(M+H)⁺ ; ¹ H NMR of the free base (CDCl₃) δ1.57-1.73 (1H, m), 1.87-1.97(1H, m), 2.13-2.24 (1H, m), 2.38 (3H, s), 2.5-2.65 (1H, m), 2.68-2.88(2H, m), 2.87-3.0 (3H, m), 3.15-3.23 (1H, m), 3.29-3.39 (1H, m),6.87-7.3 (8H, m). Analysis calculated for C₂₀ H₂₃ ClFN: C, 72.39; H,6.99; N, 4.22. Found: C, 71.91; H, 6.95; N, 4.12.

EXAMPLE 17 3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindole methanesulfonic acid salt Step 1:2-(4-Fluorophenyl)methyl-1,3-dithiane

1,3-Dithiane (20 g, 166 mmol) was dissolved in 250 mL of anhydrous THFunder a nitrogen atmosphere. The resultant solution was cooled to -78°C. and n-butyllithium (128 mL of a 1.5M solution of in hexane, 199 mmol) was added. The reaction mixture was warmed to 0° C. and thenstirred at 0° C. for 0.5 h. The reaction mixture was recooled to -78° C.and 25 g (0.135 mol) of 3-fluorobenzyl bromide was added over a 15minute period. The reaction mixture was stirred for 3 h at ambienttemperature and then the reaction was quenched with aqueous ammoniumchloride solution. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was distilled to afford 35.5 g (94% yield)of the title compound, b.p. 125°-145° C. (0.75 mm Hg); MS DCl--NH₃ M/Z:229 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.76-1.95 (1H, m), 2.05-2.19 (1H, m),2.78-2.98 (4H, m), 2.99 (2H, d, J=9 Hz), 4.21 (1H, t, J=9 Hz), 6.93-7.05(2H, m), 7.16-7.25 (2H, m).

Step 2:1-Cyano-2-[1-(13-dithiane)-2-(4-fluorophenyl)ethyl]-1,2,3,4-tetrahydronaphthalene

2-(4-Fluorophenyl)methyl-1,3-dithiane (16.2 g, 70.9 mmol), from Step 1,was dissolved in 100 mL of anhydrous THF and the resultant solution wascooled to 0° C. n-Butyl lithium (28.4 mL of a 2.5M solution in hexane)was added and the resultant solution was added to a solution of 10 g(64.4 mmol) of 1-cyano-3,4-dihydronaphthalene (the product of Step 1 ofExample 9) in 100 mL of anhydrous THF at -78° C. The reaction mixturewas allowed to warm to ambient temperature, stirred at ambienttemperature for 2 h and then the reaction was quenched with concentratedaqueous ammonium chloride solution. The resultant layers were separatedand the aqueous layer was extracted with two portions of ethyl acetate.The combined organic extracts were washed with brine, dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel eluted with 8:1hexane:ethyl acetate to give 8.4 g (34 % yield) of the title compound asa yellow foam; MS DCl--NH₃ M/Z: 384 (M+H)⁺, 401 (M+NH₄)⁺ ; ¹ H NMR(CDCl₃) δ1.56-2.19 (4H, m), 2.42-3.22 (7H, m), 3.04, 3.71 (2H, dd, J=15Hz), 4.51 (1H, dd, J=5 Hz, 1.5 Hz), 6.88-7.44 (8H, m).

Step 3:1-Cyano-2-[1-(1,3-dioxolane)-2-(4-fluorophenyl)ethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 4 of Example 1, replacing1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 8.4 g (21.9 mmol) of1-cyano-2-[1-(13-dithiane)-2-(4-fluorophenyl)ethyl]-1,2,3,4-tetrahydronaphthalene,from Step 2 of this Example, the title compound was prepared; MSDCl--NH₃ M/Z: 338 (M+H)⁺, 355 (M+NH₄)⁺.

Step 4:1-Aminomethyl-2-[1-(1,3-dioxolane)-2-(4-fluorophenyl)ethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 5 of Example 1, replacing1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 4.7 g (14 mmol) of1-cyano-2-[1-(1,3-dioxolane)-2-(4-fluorophenyl)ethyl]-1,2,3,4-tetrahydronaphthalene,from Step 3 of this Example, the title compound was prepared.

Step 5:3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindolemethanesulfonic acid salt

1-Aminomethyl-2-[1-(1,3-dioxolane)-2-(4-fluorophenyl)ethyl]1,2,3,4-tetrahydronaphthalene(3.35 g (9.8 mmol), from Step 4 of this Example, was dissolved in 120 mLof THF and 60 mL of 3N aqueous hydrochloric acid solution was added tothe resultant solution. The reaction mixture was heated at 80° C. for 1h. The solvents were removed in vacuo and 250 mL of methanol was addedto the residue. A solution of sodium cyanoborohydride (1.85 g, 29.4mmol) in 40 mL of methanol was added dropwise to the resultant solution.After removing the solvent in vacuo, the residue was dissolved in waterand 45% aqueous sodium hydroxide solution was added until the solutionwas basic on litmus paper. The resultant layers were separated and theaqueous layer was extracted with three portions of methylene chloride.The combined organic extracts were dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel eluted with ethylacetate:water:formic acid (18:1:1) to give the formic acid salt of thetitle compound. The formic acid salt was treated with a solution ofmethanesulfonic acid in acetone/diethyl ether to give the titlecompound; MS DCl--NH₃ M/Z: 282(M+H)⁺ ; ¹ NMR (CDCl₃) δ1.45-1.63 (1H, m),1.83-1.95 (1H, m), 2.2-2.33 (1H, m), 2.53-3.0 (5H, m), 3.33-3.53 (2H,m), 3.0-3.68 (1H, m), 6.85-7.2 (7H, m), 7.2-7.32 (1H, m). Analysiscalculated for C₂₁ H₂₆ FNO₃ S: C, 63.64; H, 6.41; N, 3.71. Found: C,63.37 ; H, 6.45; N, 3.65.

EXAMPLE 18cis-3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Example 2, replacing the productof Example 1 with the product of Step Example 17, the title compound wasprepared as a mixture of the cis and trans isomers. The cis-anti productwas isolated by chromatography on silica gel eluted with 2:1hexane:diethyl ether saturated with ammonia and converted to themethanesulfonic acid salt; MS DCl--NH₃ M/Z: 296 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ1.82-2.09 (2H, m), 2.47-3.01 (3H, m), 2.79 (3H, s), 2.84 (3H, d, J=5Hz), 3.18-3.40 (3H, m), 3.57-3.71 (2H, m), 3.92-4.06 (1H, m), 6.94-7.22(6H, m), 7.33-7.42 (2H, m). Analysis calculated for C₂₁ H₂₆ FNO₃ S: C,64.43; H, 6.69; N, 3.58. Found: C, 64.34; H, 6.73; N, 3.55.

EXAMPLE 19trans-2,3,3a,4,5,9b-Hexahydro-3-(3-methoxyphenyl)methyl-1H-benz[e]isoindolehydrochloride Step 1: 2-(3-Methoxyphenyl)methyl-1,3-dithiane

Following the procedures described in Step 1 of Example 1, replacingphenylacetaldehyde with 21.6 g (158.6 mmol) of3-methoxyphenylacetaldehyde, the title compound was prepared in 28%yield (17.5 g), m.p. 54°-56° C.; MS DCl--NH₃ M/Z: 391 (M+H)⁺.

Step 2:1-Cyano-2-[1-(13-dithiane)-2-(3-methoxyphenyl)ethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 2 of Example 17, replacing2-(4-fluorophenyl)methyl-1,3-dithiane with 18.57 g (77.37 mmol) of2-(3-methoxyphenyl)methyl-1,3-dithiane, from Step 1, the title compoundwas prepared in 35% yield (9.2 g); MS DCl--NH₃ M/Z: 396 (M+H)⁺, 413(M+NH₄)⁺.

Step 3:1-Cyano-2-(3-methoxyphenyl)methylcarbonyl-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 1 of Example 6, replacing1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 8.85 g (22.4 mmol) of1-cyano-2-[1-(1,3-dithiane)-2-(3-methoxyphenyl)ethyl]-1,2,3,4-tetrahydronaphthalene(the product of Step 2) the title compound was prepared in 67% yield (4g); MS DCl--NH₃ M/Z: 306 (M+H)⁺, 323 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃)δ2.1-2.28 (1H, m), 2.3-2.42 (1H, m), 2.77-3.5 (3H, m), 3.8 (3H, s),3.85-3.92 (2H, m), 4.08-4.2 (1H, m), 6.77-6.9 (3H, m), 7.1-7.3 (5H, m).

Step 4:trans-2,3,3a,4,5,9b-Hexahydro-3-(3-methoxyphenyl)methyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Step 2 of Example 6, replacing1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalene(the product of Step 1 of Example 6) with 4 g (13.15 mmol) of theproduct of Step 3 above,1-cyano-2-(3-methylphenyl)methylcarbonyl-1,2,3,4-tetrahydronaphthalene,the desired compound was prepared as the hydrochloride salt in 60% yield(2.2 g), m.p. 210°-212 ° C.; MS DCl--NH₃ M/Z: 294 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ1.5-1.78 (1H, m), 1.88-1.98 (1H, m), 2.68-2.78 (1H, m),2.88-3.0 (4H, m), 3.14-3.25 (1H, m), 3.5-3.6 (1H, m), 3.8 (3H, s),6.72-7.0 (4H, m), 7.05-7.25 (4H, m). Analysis calculated for C₂₀ H₂₄ClNO: C, 72.83; H, 6.98; N, 4.24. Found: C, 72.74; H, 7.38; N, 4.19.

EXAMPLE 20trans-2,3,3a,4,5,9b-Hexahydro-3-(3-methoxyphenyl)methyl-2-methyl-1H-benz[e]isoindolehydrochloride

A solution of 1.3 g (4.43 mmol) of2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindole(the product of Example 19) and 5 mL of formalin (37% aqueousformaldehyde solution) in 95 mL of methanol was hydrogenated at ambienttemperature and 4 atmospheres of hydrogen for 24 h in the presence of0.65 g of 20% palladium on carbon. The hydrogenation mixture wasfiltered and the filtrate was concentrated in vacuo. The residue wasadsorbed on silica gel and chromatographed on silica gel eluted withethyl acetate:formic acid:water (18:1:1) to give the formic acid salt ofthe desired product which was converted to the free the amine product.The amine was converted to the title compound by treatment with hydrogenchloride in methanol solution, m.p. 188°-19° C.; MS DCl--NH₃ M/Z: 208(M+H)⁺ ; ¹ H NMR of the methanesulfonic acid salt (CDCl₃) δ1.43-1.5 (1H,m), 1.74-1.84 (1H, m), 2.0-2.15 (1H, m), 2.72 (3H, s), 2.88-2.98 (2H,m), 3.04-3.18 (3H, m), 3.3-3.52 (2H, m), 3.75-3.85 (1H, m), 3.82 (3H,s), 6.78-6.92 (4H, m), 7.08-7.3 (4H, m). Analysis calculated for C₂₁ H₂₆ClNO: C, 73.63; H, 7.28; N, 4.07. Found: C, 72.82; H, 7.62; N, 4.00.

EXAMPLE 21cis-2,3,3a,4,5,9b-Hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt Step 1:1-Cyano-5-methoxy-3,4-dihydronaphthalene

Following the procedures described in Step 2 of Example 1, replacing6-methoxy-α-tetralone with 5-methoxy-α-tetralone (commercially availablefrom Aldrich Chemical Company), the title compound was prepared.

Step 2:1-Cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalene

2-Benzyl-1,3-dithiane (18.7 g, 89 mmol), the product of Step 1 ofExample 1, was dissolved in 200 mL of anhydrous THF under a nitrogenatmosphere and the resultant solution was cooled to 0° C. To the stirredsolution was slowly added n-butyllithium (35.6 mL of a 2.5M solution inhexane) and the resultant solution was stirred for 1.5 h at 0° C. Thesolution was then cooled to -78° C. and a solution of 15 g (81 mmol) of1-cyano-5-methoxy-3,4-dihydronaphthalene (the product of Step 1 of thisExample) in 150 mL of anhydrous THF was added in a continuous stream viacannula. The reaction mixture was allowed to warm to ambient temperatureand, after stirring at ambient temperature for 3 h, the reaction wasquenched by the addition of saturated aqueous ammonium chloridesolution. The resultant layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo.Trituration with diethyl ether gave 17.4 of the title compound. Theether solution was concentrated and the residue was purified bychromatography on silica gel eluted with 6:1 hexane:ethyl acetate togive another 11.4 g of the title compound, for a total of 28.8 g (90%yield) of the desired product; MS DCl--NH₃ M/Z: 396 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ1.70-2.18 (3H, m), 2.49-2.78 (6H, m), 2.85-2.96 (1H, m),3.07-3.19 (1H, m), 3.12, 3.72 (2H, dd, J=15 Hz), 3.84 (3H, s), 4.49 (1H,dd, J=1.5 Hz, 4.5 Hz), 6.78 (1H, d, J=8 Hz), 6.91 (1H, d, J=8 Hz), 7.20(1H, t, J=8 Hz), 7.24-7.43 (5H, m).

Step 3:1-Cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalene

A mixture of 12 g (30.3 mmol) of1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalenefrom Step 2, 25 g (91 mmol) of mercury chloride and 75 mL of ethyleneglycol in 75 mL of THF was refluxed under a nitrogen atmosphere for 7 h.The reaction mixture was allowed to cool to ambient temperature, dilutedwith 600 mL of methylene chloride and filtered through Celite filteraid. The filter cake was washed with methylene chloride and the combinedfiltrates were concentrated to give a mixture of a yellow oil and apurple semi-solid material. The oil was separated and partitionedbetween methylene chloride and water (4:1 v/v). The organic layer wassaved and the aqueous layer was extracted with methylene chloride. Thepurple material was also partitioned between methylene chloride andwater (4:1 v/v). The organic layer was again saved and the aqueous layerwas extracted with two portions of methylene chloride. All of theorganic layers were then combined, washed with two portions of water andthen absorbed onto silica gel. The silica gel was dried under reducedpressure (on the rotory evaporator) and loaded onto a silica gel columnwhich was then eluted with 6:1 hexane:ethyl acetate to give 6.2 g (58%)of the title compound; MS DCl--NH₃ M/Z: 350 (M+H)⁺, 367 (M+H₄)⁺ ; ¹ HNMR (CDCl₃) δ1.97-2.60 (4H, m), 2.92-3.21 (1H, m), 2.98, 3.12 (2H, dd,J=15 Hz), 3.50-4.18 (5H, m), 3.81 (3H, s), 6.73 (1H, d, J=8 Hz), 6.82(1H, d, J=8 Hz), 7.05-7.39 (6H, m).

Step 4:1-Aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 5 of Example 1, replacing1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalene,from Step 3 above, the title compound was prepared; MS DCl--NH₃ M/Z: 354(M+H)⁺.

Step 5:cis-2,3,3a,4,5,9b-Hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

1-Aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalene(6.0 g, 17.0 mmol), from Step 4, was dissolved in 240 mL of THF, 120 mLof 3N aqueous hydrochloric acid solution was added at ambienttemperature and the resultant solution was heated at reflux temperatureovernight. The solvents were removed in vacuo and the residue wasdissolved in 150 mL of methanol. To the resultant methanol solution wasadded a solution of 3 g in 40 mL of methanol, dropwise over a 20 minuteperiod. The reaction mixture was stirred at ambient temperature for 15minutes and then concentrated in vacuo. The residue was partitionedbetween 15% aqueous potassium hydroxide solution and methylene chloride(1:5 v/v) and the aqueous layer was extracted with two portions ofmethylene chloride. The combined organic layers were concentrated invacuo. The residue was treated with methanol saturated with anhydroushydrogen chloride and the solution was concentrated in vacuo. Theresidue was dried with toluene three times and then dissolved in hotacetone. The crystals which precipitated upon cooling to ambienttemperature were dissolved in aqueous potassium hydroxide solution andthe aqueous solution was extracted with four portions of methylenechloride. The combined organic layers were dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The free base wasconverted to the title compound using 1.1 equivalents of methanesulfonicacid in diethyl ether/acetone, m.p. 129.5°-131.0° C.; MS DCl--NH₃ M/Z:294 (M+H)⁺ ; ¹ H NMR of the free base (CDCl₃) δ1.36-1.54 (1H, m), 1.69(1H, bs), 1.87-1.99 (1H, m), 2.12-2.41 (2H, m), 2.71-3.12 (4H, m),3.28-3.49 (2H, m), 3.58-3.68 (1H, m), 3.81 (3H, s), 6.65 (1H, d, J=8Hz), 6.68 (1H, d, J=8 Hz), 7.08 (1H, t, J=8 Hz), 7.16-7.34 (5H, m).Analysis calculated for C₂₁ H₂₇ NO₄ S: C, 64.79; H, 6.99; N, 4.00.Found: C, 64.63; H, 6.99; N, 3.49.

EXAMPLE 22 cis-2,3,3a,4,5,9b-Hexahydro-6-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Example 2, replacing the productof Example 1 with the product of Example 21, the title compound wasprepared, m.p. 170°-171° C.; MS DCl--NH₃ M/Z: 308 (M+H)⁺ ; ¹ H NMR ofthe free base (CDCl₃) δ1.51-1.68 (1H, m), 1.97-2.30 (3H, m), 2.40 (3H,s), 2.72-3.08 (5H, m), 3.16-3.35 (2H, m), 3.80 (3H, s), 6.64 (1H, d, J=8Hz), 6.66 (1H, d, J=8 Hz), 7.08 (1H, t, J=8 Hz), 7.18-7.36 (5H, m).Analysis calculated for C₂₂ H₉ NO₄ S: C, 65.48; H, 7.24; N, 3.47. Found:C, 65.22; H, 7.22; N, 3.42.

EXAMPLE 23 cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindole methanesulfonicacid salt

Following the procedures described in Example 3, replacing the productof Example 1 with 2.52 g (8.59 mmol) of the free amine product ofExample 21, the title compound was prepared, m.p. 166.0°-167.1° C.; MSDCl--NH₃ M/Z: 322 (M+H)⁺ ; ¹ H NMR of the free base (CDCl₃) δ1.08 (3H,t, J=7.5 Hz), 1.54-1.72 (1H, m), 1.97-2.43 (4H, m), 2.74-3.39 (8H, m),3.80 (3H, s), 6.64 (1H, d, J=8 Hz), 6.67 (1H, d, J=8 Hz), 7.08 (1H, t,J=8 Hz), 7.16-7.35 (5H, m). Analysis calculated for C₂₃ H₃₁ NO₄ S: C,66.16; H, 7.48; N, 3.35. Found: C, 65.79; H, 7.44; N, 3.38.

EXAMPLE 24cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-2-methyl-1H-benz[e]isoindolehydrochloride Step 1:1-Cyano-2-[1-(1,3-dithiane)-2-(3-fluorophenyl)ethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 3 of Example 1, replacing1-cyano-6-methoxy-3,4-dihydronaphthalene with1-cyano-5-methoxy-3,4-dihydronaphthalene (the product of Step 1 ofExample 21) and 2-phenylmethyl-1,3-dithiane with2-(3-fluorophenyl)methyl-1,3-dithiane (the product of Step 1 of Example15), the title compound was prepared in 4.8 (68%) yield. m.p. 78°-88°C.; MS DCl--NH₃ M/Z: 414 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.72-2.14 (3H, m),2.5-3.05 (8H, m), 3.1, 3.72 (2H, dd, J=15 Hz), 3.85 (3H, s), 4.49 (1H,dd, J=4.6, 1.5 Hz), 6.8 (1H, d, J=9 Hz), 6.92 (1H, dd, J=9 Hz), 6.9-7.3(5H, m).

Step 2: 1-Cyano-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 4 of Example 1, replacing1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith1-cyano-2-[1-(13-dithiane)-2-(3-fluorophenyl)ethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalene,from Step 1 of this Example, the title compound was prepared in 46%yield m.p. 80°-82° C.; MS DCl--NH₃ M/Z: 368 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ1.95-2.28 (3H, m), 2.42-2.58 (1H, m), 2.95-3.07 (1H, m), 2.97, 3.14(2H, dd, J=15 Hz), 3.68- 3.75 (1H, m), 3.82 (3H, s), 3.88-3.98 (1H, m),4.05-4.17 (3H, m), 6.75 (1H, d, J=9.0 Hz), 6.84 (1H, d, J=9 Hz),6.88-7.25 (5H, m).

Step 3:1-Aminomethyl-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 5 of Example 1, replacing1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith1-cyano-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalene,from Step 2 of this Example, the title compound was prepared; MSDCl--NH₃ M/Z: 3724(M+H)⁺, 389 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ1.62-2.55 (4H,m), 2.83-3.1 (1H, m), 2.92, 3.07 (2H, dd, J=15 Hz), 3.6-3.8 (7H, m),3.84 (3H, s), 6.62-7.3 (7H, m).

Step 4:3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benz[e]isoindole

Following the procedures described in Step 6 of Example 1, replacing1-aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith1-aminomethyl-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-5-methoxy-1,2,3,4-tetrahydronaphthalene,from Step 3 of this Example, the title compound was prepared; MSDCl--NH₃ M/Z: 312 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.38-1.55 (1H, m), 1.85-2.0(1H, m), 2.18-2.3 (1H, m), 2.78-3.02 (5H, m), 3.0-3.15 (1H, m), 3.3-3.4(1H, m), 3.55-3.7 (1H, m), 3.8 (3H, s), 6.60-6.75 (2H, m), 6.85-7.15(4H, m), 7.2-7.3 (1H, m).

Step 5:cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-2-methyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 2, replacing the productof Example 1 with 1.6 g (5.46 mmol) of the product of Step 4 of thisExample, the title compound was prepared in 34% yield (0.6 g), m.p.226°-228° C.; MS DCl--NH₃ M/Z: 326 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.9-2.03(1H, m), 2.15-2.3 (1H, m), 2.3-2.5 (2H, m), 2.83 (3H, s), 3.0-3.13 (1H,m), 3.2-3.48 (3H, m), 3.5-3.68 (2H, m), 3.73 (3H, s), 3.88-4.00 (1H, m),6.5-6.7 (2H, m), 6.9-7.1 (4H, m), 7.15-7.4 (1H, m). Analysis calculatedfor C₂₁ H₂₅ ClF+0.25H₂ ONO_(z) : C, 68.84; H, 7.02; N, 3.82. Found: C,68.51; H, 7.00; N, 3.73.

EXAMPLE 25cis-2-Ethyl-3-(3-fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 3, replacing the productof Example 1 with the product of Step 4 of Example 24, the titlecompound was prepared, m.p. 197°-200° C.; MS DCl--NH₃ M/Z: 340 (M+H)⁺ ;¹ H NMR (CDCl₃) δ1.5 (3H, t, J=7.5 Hz), 1.58-1.7 (1H, m), 2.05-2.4 (3H,m), 2.75-3.15 (8H, m), 3.2-3.3 (1H, m), 3.8 (3H, s), 6.6-6.7 (2H, m),6.88-7.15 (4H, m), 7.2-7.3 (1H, m). Analysis calculated for C₂₂ H₂₇ClFNO+H₂ O: C, 67.07; H, 7.35; N, 3.56. Found: C, 66.75; H, 6.92; N,3.39.

EXAMPLE 26trans-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-1H-benz[e]isoindolehydrochloride Step 1:1-Cyano-2-[1-(13-dithiane)-2-(3-fluorophenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 3 of Example 1, replacing2-phenylmethyl-1,3-dithiane with 16.2 g of2-(3-fluorophenyl)methyl-1,3-dithiane, the product of Step 1 of Example15, the title compound was prepared; MS DCl--NH₃ M/Z: 414 (M+H)⁺ ; ¹ HNMR (CDCl₃) of cis isomer δ1.82-1.97 (2H, m), 2.02-2.18 (1H, m),2.44-2.97 (7H, m), 3.03-3.15 (1H, m) 3.05, 3.72 (2H, dd J=15 Hz), 3.78(3H, s), 4.45 (1H, dd, J=4.6, 1.5 Hz), 6.70 (1H, d, J=3 Hz), 6.8 (1H,dd, J=9 Hz, 3 Hz), 6.93-7.30 (5H, m).

Step 2:1-Cyano-2-(3-fluorophenyl)methylcarbonyl-6-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 1 of Example 6, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 6 g (14.53 mmol) of the product of Step 1 of this Example, thetitle compound was prepared in 57% yield (2.67 g) as a mixture of cisand trans isomers; MS DCl--NH₃ M/Z: 341 (M+NH₄)⁺.

Step 3:trans-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-1H-benz[e]isoindolehydrochloride

Following the procedures described in Step 2 of Example 6, replacing1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalenewith 2.6 g (8 mmol) of the product of Step 2 of this Example, the titlecompound was prepared in 72% yield (1.8 g), m.p. 244°-246° C.; MSDCl--NH₃ M/Z: 312(M+H)⁺ ; ¹ H NMR of the free amine (CDCl₃) δ1.44-1.6(2H, m), 1.75-1.95 (2H, m), 2.68-2.97 (5H, m), 3.16-3.27 (1H, m),3.48-3.6 (1H, m), 3.77 (3H, s), 6.6-7.3 (7H, m).

EXAMPLE 27trans-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-2-methyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 7, replacing the productof Example 6 with 1.8 g (5.8 mmol) of the product of Example 26, thedesired compound was prepared in 53% yield (1 g) as the hydrochloridesalt; MS DCl--NH₃ M/Z: 326 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.35-1.75 (3H, m),2.48 (3H, s), 2.53-2.63 (1H, m), 2.7-3.25 (7H, m), 3.75 (3H, s),6.6-7.28 (7H, m). Analysis calculated for C₂₁ H₂₅ ClFNO: C, 69.70; H,6.96; N, 3.87. Found: C, 69.21; H, 6.87; N, 3.83.

EXAMPLE 28cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-2-methyl-1H-benz[e]isoindolehydrochloride Step 1:1-Cyano-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 4 of Example 1, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith1-cyano-2-[1-(13-dithiane)-2-(3-fluorophenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 1 of Example 26, the title compound was prepared;MS DCl--NH₃ M/Z: 368 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ2.0-2.15 (3H, m),2.70-2.85 (1H, m), 2.92-3.1 (1H, m), 2.98, 3.14 (2H, dd, J=15 Hz),3.65-3.75 (1H, m), 3.78 (3H, s), 3.88-3.92 (1H, m), 4.05-4.18 (3H, m),6.65 (1H, d, J=3.0 Hz), 6.73 (1H, dd, J=9.0 Hz, 3.0 Hz), 6.9-7.3 (5H,m).

Step 2:1-Aminomethyl-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 5 of Example 1, replacing1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 2.7 g (7.35 mmol) of1-cyano-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenefrom Step 1 of this Example, the title compound was prepared in 77%yield (2.1 g); MS DCl--NH₃ M/Z: 372 (M+H)⁺.

Step 3:cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-1H-benz[e]isoindole

Following the procedures described in Step 6 of Example 1, replacing1-aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 2.4 g (6.5 mmol) of1-aminomethyl-2-[1-(1,3-dioxolane)-2-(3-fluorophenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenethe title compound was prepared in 39.5% yield (0.9 g); MS DCl--NH₃ M/Z:312 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.5-2.1 (3H, m), 2.2-2.4 (1H, m),2.57-2.99 (4H, m), 3.28-3.57 (2H, m), 3.68-3.78 (1H, m), 3.77 (3H, s),6.64 (1H, d, J=3 Hz), 6.7 (1H, dd, J=9 Hz, 3 Hz), 6.95 (1H, d, J=9 Hz),6.85-7.3 (4H, m).

Step 4: cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-methoxy-2-methyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 2, replacing2,3,3a,4,5,9b-hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindolehydrochloride with 2.6 g (8 mmol) of the product of Step 3 of thisExample, the desired product was prepared in 48% yield (0.35 g) as thehydrochloride salt; MS DCl--NH₃ M/Z: 326 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ1.6-1.8 (1H, m), 1.86-1.98 (1H, m), 2.13-2.27 (1H, m), 2.43 (3H, s),2.5-2.67 (1H, m), 2.72-3.08 (5H, m), 3.2-3.4 (2H, m), 3.77 (3H, s),6.6-7.3 (2H, m), 6.88-7.13 (4H, m), 7.23-7.33 (1H, m). Analysiscalculated for C₂₁ H₂₅ ClFNO: C, 69.7; H, 6.9; N, 3.87. Found: C, 69.48;H, 7.13; N, 3.75.

EXAMPLE 29cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-(3-methoxyphenyl)methyl-2-methyl-1H-benz[e]isoindolemethanesulfonic acid salt Step 1:1-Cyano-2-[1-(1,3-dithiane)-2-(3-methoxyphenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 2 of Example 17, replacing2-(4-fluorophenyl)methyl-1,3-dithiane with 5.01 g (20.8 mmol) of2-(3-methoxyphenyl)methyl-1,3-dithiane (the product of Step 1 of Example19), the title compound was prepared in 77% yield (6.8 g); MS DCl--NH₃M/Z: 426 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.71-1.98 (2H, m), 2.02-2.18 (1H, m),2.45-2.60 (2H, m), 2.63-3.16 (6H, m), 3.08, 3.71 (2H, dd, J=15 Hz), 3.79(3H, s), 3.81 (3H, s), 4.44 (1H, dd, J=1.5 Hz, 4.5 Hz), 6.65-6.90 (3H,m), 6.96-7.01 (2H, m), 7.13-7.26 (2H, m).

Step 2: 1-Cyano-2-[1-(1,3-dioxolane)-2-(3-methoxyphenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 4 of Example 1, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 6.5 g (15.3 mmol) of1-cyano-2-[1-(1,3-dithiane)-2-(3-methoxyphenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 1 of this Example), the title compound was preparedin 63% yield (3.69 g); MS DCl--NH₃ M/Z: 380 (M+H)⁺, 397 (M+NH₄)⁺ ; ¹ HNMR (CDCl₃) δ2.02-2.22 (3H, m), 2.69-2.85 (1H, m), 2.91-3.09 (1H, m),2.94, 3.08 (2H, dd, J=15 Hz), 3.62-3.84 (1H, m), 3.76 (3H, s), 3.78 (3H,s), 3.92-4.18 (4H, m), 6.60-6.95 (5H, m), 7.08-7.22 (2H, m).

Step 3:1-Aminomethyl-2-[1-(1,3-dioxolane)-2-(3-methoxyphenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 5 of Example 1, replacing1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 3.7 g of1-cyano-2-[1-(1,3-dioxolane)-2-(3-methoxyphenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of this Example), the title compound was preparedin 84% yield (3.15 g); ¹ H NMR (CDCl₃) δ1.37 (2H, bs), 1.51-1.68 (1H,m), 2.05-2.21 (2H, m), 2.53-3.07 (7H, m), 3.40-3.56 (2H, m), 3.65-3.95(2H, m), 3.78 (6H, s), 6.62-6.80 (3H, m), 6.84-6.93 (2H, m), 7.03-7.21(2H, m).

Step 4:2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-(3-methoxyphenyl)methyl-1H-benz[e]isoindole

Following the procedures described in Step 6 of Example 1, replacing1-aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 3.15 g (8.21 mmol) of1-aminomethyl-2-[1-(1,3-dioxolane)-2-(3-methoxyphenyl)ethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 3 of this Example), the title compound was preparedin 94% yield (2.5 g); MS DCl--NH₃ M/Z 324 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ1.48-2.36 (3H, m), 2.59-3.05 (5H, m), 3.23-3.90 (3H, m), 3.79 (3H, s),3.82 (3H, s), 6.64-7.07 (6H, m), 7.20-7.31 (1H, m).

Step 5:cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-(3-methoxyphenyl)methyl-2-methyl-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Example 2, replacing the productof Example 1 with2,3,3a,4,5,9b-hexahydro-7-methoxy-3-(3-methoxyphenyl)methyl-1H-benz[e]isoindolefrom Step 4 of this Example, the desired compound was prepared as themethanesulfonic acid salt; MS DCl--NH₃ M/Z: 338 (M+H)⁺ ; ¹ H NMR of thefree base (CDCl₃) δ1.52-1.72 (1H, m), 1.88-2.01 (1H, m), 2.12-2.24 (1H,m), 2.37 (3H, s), 2.49-2.97 (6H, m), 3.10-3.32 (2H, m), 3.74 (3H, s),3.82 (3H, s), 6.58-6.97 (6H, m), 7.18-7.27 (1H, m). Analysis calculatedfor C₂₃ H₃₁ NO₅ S: C, 63.71; H, 7.21; N, 3.28. Found: C, 63.57; H, 7.27;N, 3.23.

EXAMPLE 30cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-(3-phenyl-1-propyl)-1H-benz[e]isoindolemethanesulfonic acid salt Step 1: 2-(3-Phenyl)propyl-1,3-dithiane

Following the procedures described in Step 1 of Example 1, replacingphenylacetaldehyde with 4-phenylbutanal, the title compound wasprepared, b.p. 130°-138° C. (0.3 mm Hg); MS DCl--NH₃ M/Z: 239 (M+H)⁺ ; ¹H NMR (CDCl₃) δ1.58-2.5 (6H, m), 2.6-3.4 (6H, m), 4-4.4 (1H, m), 7.2-7.7(5H, m).

Step 2:1-Cyano-2-[1-(1,3-dithiane)-4-phenylbutyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene

To a solution of 5.4 g (22.7 mmol) of 2-(3-phenyl-1-propyl)-1,3-dithiane(from Step 1) in 100 mL of anhydrous THF, at 0° C. under a nitrogenatmosphere, was added 16 mL of a 1.5M solution of n-butyllithium (24mmol) in hexane. The pale pink solution was stirred for approximately 2h at 0° C. and then was cooled to -78° C. To the solution of2-(3-phenyl-1-phenyl)-2-lithio-1,3-dithiane was then added, via cannula,a solution of 4 g (21.6 mmol) of1-cyano-6-methoxy-3,4-dihydronaphthalene, (the product of Step 2 ofExample 1), in 100 mL of THF, at -78° C. The pale yellow coloredreaction mixture was allowed to warm to -20° C., was stirred at -20° C.,under nitrogen, for 1.5 h, and then the reaction was quenched by theaddition of 50 mL of saturated aqueous ammonium chloride solution.Methylene chloride was added and the layers were separated. The organiclayer was dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The residue was dissolved in diethylether/methylene chloride and purified by flash chromatography on silicagel eluted with 1:1 hexane:diethyl ether to afford 6.14 g (67% yield) ofthe title compound; MS DCl--NH₃ M/Z: 424 (M+H)⁺, 441 (M+H₄)⁺ ; ¹ H NMR(CDCl₃) δ1.42-1.58 (1H, m), 1.67-2.04 (6H, m), 2.12-2.24 (1H, m),2.57-2.9 (9H, m), 3.78 (3H, s), 4.45 (1H, d, J=4.5 Hz), 6.67 (1H, d),6.78 (1H, dd), 7.13-7.33 (6H, m).

Step 3:1-Cyano-2-[1-(1,3-dioxolane)-4-phenylbutyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 4 of Example 1, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 4.23 g (10 mmol) of1-cyano-2-[1-(1,3-dithiane)-4-phenylbutyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of this Example), the title compound was preparedin 51% yield (1.91 g); MS DCl--NH₃ M/Z: 378 (M+H)⁺, 395 (M+H₄)⁺ ; ¹ HNMR (CDCl₃) δ1.6-2.17 (6H, m), 2.53-3.03 (5H, m), 3.77 (3H, s), 3.9-4.35(5H, m), 6.63 (1H, d, J=3 Hz), 6.75 (1H, dd, J=9 Hz), 7.1-7.4 (6H, m).

Step 4:1-Aminomethyl-2-[1-(1,3-dioxolane)-4-phenylbutyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 5 of Example 1, omitting thefinal chromatographic purification and replacing1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 1.57 g (4.2 mmol) of1-cyano-2-[1-(1,3-dioxolane)-4-phenyl-butyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 3 of this Example), the title compound was preparedin 95% yield (1.5 g); MS DCl--NH₃ M/Z: 382 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ1.3-1.9 (7H, m), 2.05-2.21 (1H, m), 2.5-3 (6H, m), 3.77 (3H, s),3.8-4.05 (4H, m), 6.6-6.7 (2H, m), 7.00-7.3 (6H, m).

Step 5:2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-(3-phenylpropyl)-1H-benz[e]isoindole

A solution of 1.5 g (3.9 mmol) of1-aminomethyl-2-[1-(1,3-dioxolane)-4-phenylbutyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 4 of this Example), in 30 mL of THF and 5 mL of 3Naqueous hydrochloric acid was stirred at ambient temperature for 1 h. Atthis time, according to TLC analysis, on silica gel plates eluted with20:1:1 ethyl acetate:water:formic acid, the reaction had gone tocompletion. The solvent was evaporated in vacuo and residual waterremoved by azeotropic distillation with benzene. The residue wasdissolved in 40 mL of methanol and 1 g of sodium cyanoborohydride wasadded to the resultant solution followed by a few crystals ofbromocresol green indicator. The pH of the solution was adjusted withmethanolic hydrogen chloride until the color of the solution changedfrom yellow to greenish blue. The solvent was removed in vacuo and theresidue was dissolved in 2N aqueous hydrochloric acid in order to quenchany excess sodium cyanoborohydride and the resultant aqueous solutionwas extracted with diethyl ether. The aqueous layer from the etherextraction was then extracted with methylene chloride. The etherextracts and the methylene chloride extracts were combined andconcentrated to afford 0.67 g (54% yield) of the title compound as amixture of the cis and trans isomers; MS DCl--NH₃ M/Z: 322 (M+H)⁺.

Step 6;cis-2,3,3a,4,5,9b-Hexahydro-7-methoxy-2-methyl-3-(3-phenylpropyl)-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Example 2, replacing the productof Example 1 with 350 mg (1.1 mmol) of2,3,3a,4,5,9b-Hexahydro-7-methoxy-3-(3-phenylpropyl)-1H-benz[e]isoindole,the product of Step 5 of this Example, the title compound was preparedin 89% yield (301 mg), m.p. 129°-131° C.; MS DCl--NH₃ M/Z: 336 (M+H)⁺ ;Analysis calculated for C₂₄ H₃₃ NO₄ S+H₂ O: C, 64.11; H, 7.85; N, 3.12.Found: C, 63.98; H, 7.36; N, 2.96.

EXAMPLE 31cis-5,6-Dimethoxy-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-1H-benz[e]isoindolehydrochloride Step 1:1-Cyano-5,6-dimethoxy-2-[1-(1,3-dithiane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 3 of Example 1, replacing1-cyano-6-methoxy-3,4-dihydronaphthalene with 15.72 g (75 mmol) of1-cyano-5,6-dimethoxy-3,4-dihydronaphthalene (prepared as described byF. Z. Basha, et al. in J. Organic Chemistry, 50: 4160-2 (1985)), thetitle compound was prepared in 44% yield (14 g), m.p. 78°-80° C.; MSDCl--NH₃ M/Z: 440 (M+H)⁺ ; ¹ H NMR (CDCl₃) of cis isomer δ1.72-1.97 (2H,m), 1.97-2.15 (1H, m), 2.45-2.97 (7H, m), 3.13, 3.74 (2H, dd J=15 Hz),3.15-3.28 (1H, m), 3.83 (3H, s), 3.89 (3H, s), 4.47 (1H, dd, J=4.6, 1.5Hz), 6.83 (1H, d, J=9 Hz), 7.04 (1H, d, J=9 Hz), 7.12-7.45 (5H, m).

Step 2:1-Cyano-5,6-dimethoxy-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 4 of Example 1, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 13.5 g of1-cyano-5,6-dimethoxy-2-[1-(1,3-dithiane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene(the product of Step 1 of this Example), the title compound was preparedin 61% yield (7.3 g), m.p. 122°-125° C.; MS DCl--NH₃ M/Z: 380 (M+H)⁺,397 (M+NH₄)⁺.

Step 3:1-Aminomethyl-5,6-dimethoxy-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 5 of Example 1, replacing1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 7.3 g (19.26 mmol) of1-cyano-5,6-dimethoxy-2-[1-(1,3-dioxolane)-2-phenyl-ethyl]-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of this Example), the title compound was preparedin 89% yield (6.5 g); MS DCl--NH₃ M/Z: 384 (M+H)⁺.

Step 4:cis-6,7-Dimethoxy-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Step 6 of Example 1, replacing1-aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 6.5 g (17 mmol) of1-aminomethyl-5,6-dimethoxy-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene(the product of Step 3 of this Example), the title compound wasprepared, m.p. 225°-226° C.; MS DCl--NH₃ M/Z: 324 (M+H)⁺ ; ¹ H NMR ofthe free amine (CDCl₃) d 1.4-1.57 (1H, m), 1.9-2.01 (1H, m), 2.15-2.25(1H, m), 2.35-2.5 (1H, m), 2.78-3.17 (3H, m), 3.08-3.2 (1H, m),3.28-3.48 (2H, m), 3.64-3.74 (1H, m), 3.8 (3H, s), 3.84 (3H, s), 6.73(1H, d, J=9 Hz), 6.78 (1H, d, J=9 Hz), 7.17-7.34 (5H, m). Analysiscalculated for C₂₁ H₂₆ ClNO₂ : C, 70.08; H, 2.28; N, 3.89. Found: C,69.94; H, 7.33; N, 3.88.

EXAMPLE 32cis-6,7-Dimethoxy-2,3,3a,4,5,9b-hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 2, replacing the productof Example 1 with 2.1 g (6.5 mmol) of the product of Example 31, thetitle compound was prepared in 50% yield (1.2 g), m.p. 243°-244° C.; MSDCl--NH₃ M/Z: 338(M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.5-1.68 (1H, m), 1.96-2.1(3H, m), 2.43 (3H, s), 2.77-3.33 (7H, m), 3.76 (3H, s), 3.84 (3H, s),6.73 (1H, d, J=9 Hz), 6.76 (1H, d, J=9 Hz), 7.16-7.36 (5H, m). Analysiscalculated for C₂₂ H₂₈ ClNO₂ +0.5H₂ O: C, 69.01; H, 7.63; N, 3.66.Found: C, 68.99; H, 7.52; N, 3.67.

EXAMPLE 33trans-6,7-Dimethoxy-2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindolemethanesulfonic acid salt Step 1:1-Cyano-5,6-dimethoxy-2-[1-(1,3-dithiane)-2-(3-methylphenyl)ethyl-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 3 of Example 1, replacing2-phenylmethyl-1,3-dithiane with 2-(3-methylphenyl)methyl-1,3-dithiane(the product of Step 1 of Example 11) and1-cyano-6-methoxy-3,4-dihydronaphthalene with1-cyano-5,6-dimethoxy-3,4-dihydronaphthalene (the product of Step 1 ofExample 31), the title compound was prepared.

Step 2:1-Cyano-5,6-dimethoxy-2-(3-methylphenyl)methylcarbonyl-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 1 of Example 6, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 8 g (18.8 mmol) of1-cyano-5,6-dimethoxy-2-[1-(1,3-dithiane)-2-(3-methylphenyl)ethyl]-1,2,3,4-tetrahydronaphthalene(the product of Step 1 of this Example), the title compound was preparedin 73% yield (4.7 g); MS DCl--NH₃ M/Z: 367 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃)δ2.0-2.45 (2H, m), 2.35 (2H, s), 2.63-3.08 (4H, m), 3.8 (3H, s), 3.86(3H, s), 4.08-4.15 (1H, m), 6.8 (1H, d, J=9 Hz), 6.9-7.28 (5H, m).

Step 3:trans-6,7-Dimethoxy-2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Step 2 of Example 6, replacing1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalenewith 4.7 g (12.84 mmol) of1-cyano-5,6-dimethoxy-2-(3-methylphenyl)methyl-carbonyl-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of this Example), the title compound was preparedin 44% yield (0.45 g), m.p. 145°-146° C.; MS DCl--NH₃ M/Z: 324 (M+H)⁺ ;¹ H NMR (CDCl₃) δ1.32-1.86 (3H, m), 2.3 (3H, s), 2.63-2.82 (1H, m),2.88-3.3 (5H, m), 3.4-3.8 (2H, m), 3.8 (3H, s), 3.86 (3H, s), 6.58 (1H,d, J=9 Hz), 6.72 (1H, d, J=9 Hz), 7.0-7.22 (4H, m). Analysis calculatedfor C₂₃ H₃₁ NO₅ S+0.25H₂ O: C, 63.06; H, 7.25; N, 3.20. Found: C, 63.01;H, 7.17; N, 3.17.

EXAMPLE 34trans-6,7-Dimethoxy-2,3,3a,4,5,9b-hexahydro-2-methyl-3-(3-methylphenyl)methyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 7, replacing the productof Example 6 with 1.17 g (3.62 mmol) of the product of Example 33, thedesired product was prepared and converted to the hydrochloride salt(the title compound), m.p. 100°-104° C.; MS DCl--NH₃ M/Z: 352 (M+H)⁺.Analysis calculated for C₂₃ H₃₀ ClNO₂ +H₂ O: C, 68.05; H, 7.95; N, 3.45.Found: C, 64.47; H, 7.57; N, 3.34.

EXAMPLE 35trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-6,7-methylenedioxy-3-(3-methylphenyl)methyl-1H-benz[e]isoindolemethanesulfonic acid salt Step 1:1-Cyano-2-[1-(1,3-dithiane)-2-(3-methylphenyl)ethyl]-5,6-methylenedioxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 2 of Example 17, replacing2-(4-fluorophenyl)methyl-1,3-dithiane with 6.19 g (27.6 mmol) of2-(3-methylphenyl)methyl-1,3-dithiane and 1-cyano-3,4-dihydronaphthalenewith 5 g (25.1 mmol) of1-cyano-5,6-methylenedioxy-3,4-dihydronaphthalene (prepared as describedby F. Z. Basha, et al. in J. Organic Chemistry, 50: 4160-2 (1985)), thetitle compound was prepared in 77% yield (8.11 g); MS DCl--NH₃ M/Z: 424(M+H)⁺, 441 (M+NH₄)⁺.

Step 2:1-Cyano-5,6-methylenedioxy-2,3-(3-methylphenyl)methylcarbonyl-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 1 of Example 6, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 8.11 g (19.15 mmol) of1-cyano-2-[1-(1,3-dithiane)-2-(3-methylphenyl)ethyl]-5,6-methylenedioxy-1,2,3,4-tetrahydronaphthalenefrom Step 1, the title compound was prepared in 69% yield (4.43 g); MSDCl--NH₃ M/Z: 351 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ2.04-2.22 (1H, m), 2.32-2.44(1H, m), 2.35 (3H, s), 2.61-2.74 (1H, m), 2.87-2.98 (2H, m), 3.85 (2H,s), 4.11 (1H, d, J=4.5 Hz), 5.97 (2H, d, J=2 Hz, 8 Hz), 6.69 (1H, d, J=8Hz), 6.77 (1H, d, J=8 Hz), 6.99-7.12 (3H, m), 7.23 (1H, t, J=8 Hz).

Step 3:2,3,3a,4,5,9b-Hexahydro-6,7-methylenedioxy-3-(3-methylphenyl)methyl-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Step 2 of Example 6, replacing1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalenewith 4.43 g (13.3 mmol) of1-cyano-5,6-methylenedioxy-2-(3-methylphenyl)methyl-carbonyl-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of this Example), the title compound was preparedin 90% yield (3.83 g), m.p. 163°-169° C.; MS DCl--NH₃ M/Z: 322 (M+H)⁺ ;¹ H NMR (CDCl₃) δ1.40-1.61 (2H,m), 1.82 (1H, bs), 1.91-2.01 (1H, m),2.35 (3H, s), 2.58-2.97 (6H, m), 3.11-3.22 (1H, m), 3.46-3.54 (1H, m),5.92 (2H, s), 6.42 (1H, dd, J=8 Hz, 2 Hz), 6.62 (1H, d, J=8 Hz),7.0-7.10 (3H, m), 7.15-7.23 (1H, m). Analysis calculated for C₂₂ H₂₇ NO₅S+0.25H₂ O: C, 62.61; H, 6.57; N, 3.32. Found: C, 62.62; H, 6.42; N,3.25.

Step 4:trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-6,7-methylenedioxy-3-(3-methylphenyl)methyl-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Example 2, replacing the productof Example 1 with 2.27 g (7.07 mmol) of2,3,3a,4,5,9b-hexahydro-6,7-methylenedioxy-3-(3-methylphenyl)methyl-1H-benz[e]isoindolefrom Step 3 of this Example, the title compound was prepared, m.p.161.5-162.5° C.; MS DCl--NH₃ M/Z: 336 (M+H)⁺ ; ¹ NMR (CDCl₃) δ1.23-1.78(3H, m), 2.33 (3H, s), 2.47 (3H, s), 2.51-3.23 (8H, m), 5.90 (2H, s),6.37 (1H, dd, J=2 Hz, 8 Hz), 6.61 (1H, d, J=8 Hz), 6.97-7.08 (3H, m),7.17 (1H, t, J=8 Hz). Analysis calculated for C₂₃ H₂₉ NO₅ : C, 64.02; H,6.77; N, 3.25. Found: C, 63.73; H, 6.49; N, 3.21.

EXAMPLE 36trans-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7-methylenedioxy-1H-benz[e]isoindolemethanesulfonic acid salt Step 1:1-Cyano-2-[1-(1,3-dithiane)-2-(3-fluorophenyl)ethyl]-5,6-methylenedioxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 3 of Example 1, replacing1-cyano-6-methoxy-3,4-dihydronaphthalene with 6.7 g (33.6 mmol) of1-cyano-5,6-methylenedioxy-3,4-dihydronaphthalene (prepared as describedby F. Z. Basha, et al. in J. Organic Chemistry, 1985, 50: 4160-2 and 2-phenylmethyl-1,3-dithiane with 13 g (56.9 mmol) of2-(4-fluorophenyl)methyl-1,3-dithiane, the title compound was preparedin 44% yield (6.3 g); MS DCl--NH₃ M/Z: 428 (M+H)⁺.

Step 2:1-Cyano-2-(3-fluorophenyl)methylcarbonyl-5,6-methylenedioxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 1 of Example 6, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 6.3 g (14.7 mmol) of1-cyano-2-[1-(1,3-dithiane)-2-(3-fluorophenyl)ethyl]-5,6-methylenedioxy-1,2,3,4-tetrahydronaphthalenefrom Step 1, the title compound was prepared in 29% yield (1.43 g); MSDCl--NH₃ M/Z: 355 (M+H)+; ¹ H NMR of trans isomer (CDCl₃) δ2.08-2.25(1H, m), 2.34-2.46 (1H, m), 2.63-2.78 (1H, m), 2.87-3.00 (2H, m), 3.91(2H, s), 4.15 (1H, d, J=4 Hz), 5.97 (2H, dd, J=1 Hz, 6 Hz), 6.70 (1H, d,J=8 Hz), 6.78 (1H, d, J=8 Hz), 6.92-7.04 (3H, m), 7.27-7.37 (1H, m); ¹ HNMR of cis isomer (CDCl₃) δ1.70-1.86 (1H, m), 2.16-2.28 (1H, m),2.63-3.04 (2H, m), 3.16-3.25 (1H, m), 3.92 (2H, d, J=3.5 Hz), 4.28 (1H,d, J=10 Hz), 5.93-5.99 (2H, m), 6.65-6.90 (2H, m), 6.88-7.06 (3H, m),7.28-7.37 (1H, m).

Step 3:3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6,7-methylenedioxy-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Step 2 of Example 6, replacing1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalenewith 1.43 g (13.3 mmol) of1-cyano-5,6-methylenedioxy-2-(3-methylphenyl)methyl-carbonyl-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of this Example), the title compound was preparedin 30% yield (0.42 g); MS DCl--NH₃ M/Z: 326 (M+H)⁺.

Step 4: trans3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7-methylenedioxy-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Example 2, replacing the productof Example 1 with3-(3-fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6,7-methylenedioxy-1H-benz[e]isoindolefrom Step 3 of this Example, the title compound was prepared, m.p.188°-189° C.; MS DCl--NH₃ M/Z: 340 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.29-1.64(2H, m), 1.68-1.80 (1H, m), 2.45 (3H, s), 2.51-2.95 (6H, m), 2.97-3.22(2H, m), 5.90 (2H, s), 6.36 (1H, dd, J=2 Hz, 8 Hz), 6.60 (1H, d, J=8Hz), 6.85-7.08 (3H, m), 7.18-7.28 (1H, m). Analysis calculated for C₂₂H₂₆ FNO₅ S: C, 60.67; H, 6.02; N, 3.22. Found: C, 60.39; H, 6.02; N,3.17.

EXAMPLE 37cis-2,3,3a,4,5,9b-Hexahydro-6-methoxy-9-methy-3-phenylmethyl-1H-benz[e]isoindolehydrochloride Step 1: 1-Cyano-5-methoxy-8-methyl-3,4-dihydronaphthalene

Following the procedures described in Step 2 of Example 1, replacing6-methoxy-α-tetralone with 5-methoxy-8-methyl-α-tetralone (prepared asdescribed by F. Z. Basha, et al. in J. Organic Chemistry, 50: 4160-2(1985)), the title compound was prepared.

Step 2:1-Cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-5-methoxy-8-methyl-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 2 of Example 17, replacing1-cyano-6-methoxy-3,4-dihydronaphthalene with 8.2 g (41 mmol) of1-cyano-5-methoxy-8-methyl-3,4-dihydronaphthalene (the product of Step 1of this Example), the title compound was prepared in 74% yield (1.6 g),m.p. 200°-202° C.; MS DCl--NH₃ M/Z: 410 (M'H)⁺ ; ¹ H NMR (CDCl₃)δ1.72-2.2 (3H, m), 2.38 (3H, s), 2.43-2.95 (7H, m), 3.07-3.2 (1H, m),3.16, 3.75 (2H, dd, J=15 Hz), 3.82 (3H, s), 4.5 (1H, dd, J=4.6 Hz, 1.5Hz), 6.72 (1H, d, J=9 Hz), 7.04 (1H, d, J=9 Hz), 7.25-7.43 (5H, m).

Step 3: 1-Cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-5-methoxy-8-methyl-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 4 of Example 1, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 12.8 g (31.3 mmol) of1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-5-methoxy-8-methyl-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of this Example), the title compound was preparedin 62.5% yield (7.1 g); MS DCl--NH₃ M/Z: 364 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ1.97-2.28 (3H, m), 2.32 (3H, s), 2.42-2.62 (1H, m), 2.94-3.07 (1H, m),3.0, 3.13 (2H, dd, J=15 Hz), 3.6-4.18 (5H, m), 3.8 (3H,s), 6.67 (1H, d,J=9 Hz), 7.0 (1H, d, J=9 Hz), 7.17-7.35 (5H, m).

Step 4:1-Aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-5-methoxy-8-methyl-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 5 of Example 1, replacing1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 6.9 g (19 mmol) of1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-5-methoxy-8-methyl-1,2,3,4-tetrahydronaphthalene(the product of Step 3 of this Example), the title compound was preparedin 52% yield (3.6 g), m.p. 134°-136° C.; MS CDl--NH₃ M/Z: 368 (M+H)⁺.

Step 5:cis-2,3,3a,4,5,9b-Hexahydro-6-methoxy-9-methyl-3-phenylmethyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Step 6 of Example 1, replacing1-aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 1.8 g (5.1 mmol) of1-aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-5-methoxy-8-methyl-1,2,3,4-tetrahydronaphthalene(the product of Step 4 of this Example), the title compound was preparedin 62% yield (1.1 g), m.p. 240°-242° C.; MS DCl--NH₃ M/Z: 308 (M+H)⁺ ; ¹H NMR (CDCl₃) δ1.48-1.56 (1H, m), 1.9-2.45 (3H, m), 2.24 (3H, s),2.74-3.15 (4H, m), 3.3-3.72 (3H, m), 3.8 (3H, s), 6,62 (1H, d, J=9 Hz),6.95 (1H, d, J=9 Hz), 7.18-7.4 (5H, m). Analysis calculated for C₂₁H.sub. 26 ClNO+0.25H₂ O: C, 72.40; H, 7.67; N, 4.02. Found: C, 72.53; H,7.52; N, 4.09.

EXAMPLE 38cis-2,9-Dimethyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 2, replacing the productof Example 1 with 0.6 g (1.75 mmol) of the product of Example 37, thetitle compound was prepared in 65% yield (0.4 g), m.p. 183°-185° C.; MSDCl--NH₃ M/Z: 322 (M+H)⁺ ; ¹ H NMR of free base (CDCl₃) δ1.5-1.82 (2H,m), 1.98-2.32 (2H, m), 2.18 (3H, s), 6.6 (1H, d, J=9 Hz), 6.93 (1H, d,J=9 Hz), 7.17-7.35 (5H, m). Analysis calculated for C₂₂ H₂₈ ClNO+0.5H₂O: C, 72.01; H, 7.69; N, 3.82. Found: C, 71.98; H, 7.83; N, 3.85.

EXAMPLE 39cis-2-Ethyl-9-(4-(4-fluorophenyl)butyloxy)-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt Step 1:1-Cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-8-(4-(4-fluorophenyl)-1-n-butoxy)-5-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 2 of Example 17, replacing1-cyano-3,4-dihydronaphthalene with 4.3 g (12.2 mmol) of1-cyano-8-(4-(4-fluorophenyl)-1-n-butyoxy)-5-methoxy-3,4-dihydronaphthaleneand 2-(4-fluorophenyl)methyl-1,3-dithiane with 2.7 g (12.8 mmol) of2-phenylmethyl-1,3-dithiane, (the product of Step 1 of Example 1), thetitle compound was prepared in 73% yield (5 g); MS DCl--NH₃ M/Z: 562(M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.8-1.95 (5H, m), 2.0-2.12 (1H, m), 2.4-2.75(10H, m), 2.83-2.93 (1H, m), 3.08-3.2 (2H, m), 3.78 (3H, s), 3.9-4.0(1H, m), 4.05-4.13 (1H, m), 4.68-4.75 (1H, m), 6.65-6.75 (2H, m),7.2-7.35 (7H, m), 7.38-7.45 (2H, m).

Step 2:1-Cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-8-(4-(4-fluorophenyl)-1-n-butoxy)-5-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 4 of Example 1, replacing1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaph-thalenewith 5.0 g (8.9 mmol) of1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-8-(4-(4-fluorophenyl)-1-n-butoxy)-5-methoxy-1,2,3,4-tetrahydronaphthalene,from Step 1, the title compound was prepared 44% yield (2.0 g) as aclear colorless oil; MS DCl--NH₃ M/Z: 516 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ0.85-0.93 (1H, m), 1.23-1.32 (1H, m), 1.8-1.9 (3H, m), 1.92-2.0 (1H,m), 2.13-2.25 (1H, m), 2.43-2.58 (1H, m), 2.65-2.75 (2H, m), 2.95-3.15(3H, m), 3.63-3.73 (1H, m), 3.68 (3H, s), 3.85-4.2 (5H, m), 4.27-4.32(1H, m), 6.6-6.7 (2H, m), 7.15-7.33 (9H, m).

Step 3:1-Aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-8-(4-(4-fluorophenyl)-1-n-butoxy)-5-methoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 5 of Example 1, replacing1-cyano-6-methoxy-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalenewith 1.1 g (2.1 mmol) of1-cyano-2-[1-(1,3-dioxolane)-2-phenylethyl]-8-(4-(4-fluorophenyl)-1-n-butoxy)-5-methoxy-1,2,3,4-tetrahydronaphthalene,from Step 2, the title compound was prepared; MS DCl--NH₃ M/Z: 520(M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.75-1.9 (4H, m), 1.92-2.05 (1H, m), 2.63-2.73(2H, m), 2.81-2.95 (3H, m), 3.15-3.7 (10H, m), 3.75 (1H, s), 3.78 (3H,s), 3.95-4.02 (1H, m), 6.6-6.65 (2H, m), 7.1-7.28 (8H, m), 7.3-7.4 (1H,m).

Step 4: 9-(4-(4-Fluorophenyl)-1-n-butoxy)-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Step 6 of Example 1, replacing1-aminomethyl-6-methoxy-2-[1-(1,3-dioxolane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalenewith 1.25 g (2.3 mmol) of1-aminomethyl-2-[1-(1,3-dioxolane)-2-phenylethyl]-8-(4-(4-fluorophenyl)-1-n-butoxy)-5-methoxy-1,2,3,4-tetrahydronaphthalene,from Step 3, the title compound was prepared in 85% yield (0.9 g); MSDCl--NH₃ M/Z: 460 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.55-1.68 (4H, m), 1.7-1.98(5H, m), 2.0-2.15 (1H, m), 2.25-2.4 (1H, m), 2.62-3.12 (4H, m),3.35-3.48 (1H, m), 3.55-3.65 (2H, m), 3.78 (3H, s), 3.82-3.95 (2H, m),6.53-6.62 (2H, m), 7.13-7.33 (9H, m).

Step 5 :cis-2-Ethyl-9-(4-(4-fluorophenyl)butyloxy)-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

Following the procedures described in Example 3, replacing the productof Example 1 with 0.90 g (2.0 mmol) of9-(4-(4-fluorophenyl)-1-n-butoxy)-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-phenylmethyl-1H-benz[e]isoindolehydrochloride, from Step 4, the title compound was prepared as whiteneedle-like crystals, m.p. 145°-146° C.; MS DCl--NH₃ M/Z: 488 (M+H)⁺ ; ¹H NMR (CDCl₃) δ1.25 (3H, t, J=8 Hz), 1.72-1.85 (5H, m), 2.0-2.4 (3H, m),2.62-2.83 (2H, m), 2.78 (3H, s), 3.08-3.73 (8H, m), 3.75 (3H, s), 6.56(1H, d, J=9 Hz), 6.65 (1H, d, J=9 Hz), 7.1-7.4 (9H, m). Analysiscalculated for C₃₃ H₄₂ FNO₅ S: C, 67.90; H, 7.25; N, 2.40. Found: C,68.34; H, 7.39; N, 2.35.

EXAMPLE 40trans-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7,8-trimethoxy-1H-benz[e]isoindolehydrochloride Step 1:1-Cyano-2-[1-(13-dithiane)-2-(3-fluorophenyl)ethyl]-5,6,7-trimethoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 3 of Example 1, replacing1-cyano-6-methoxy-3,4-dihydronaphthalene with 9 g (36.73 mmol) of1-cyano-5,6,7-trimethoxy-3,4-dihydronaphthalene (prepared as describedby F. Z. Basha, et al. in J. Organic Chemistry, 50: 4160-2 (1985)), thetitle compound was prepared in 29% yield (6.5 g), m.p. 65°-67° C.; MSDCl--NH₃ M/Z: 474 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.68-1.82 (2H, m), 2.18-2.30(1H, m), 2.55-2.88 (4H, m), 3.13-3.26 (1H, m), 3.85 (6H, s), 3.88 (3H,s), 3.89-4.0 (5H, m), 4.32 (1H, d, J=9 Hz), 6.72 (1H, s), 6.92-7.08 (3H,m), 7.28-7.4 (1H, m).

Step 2: 1-Cyano-2-(3-fluorophenyl)methylcarbonyl-5,6,7-trimethoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 1 of Example 6, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 6.5 g (13.7 mmol) of1-cyano-2-[1-(13-dithiane)-2-(3-fluorophenyl)ethyl]-5,6,7-trimethoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 1 of this Example), the title compound was preparedin 45% yield, m.p. 120°-122° C.

Step 3:trans-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6,7,8-trimethoxy-1H-benz[e]isoindole

Following the procedures described in Step 2 of Example 6, replacing1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalenewith 0.94 g (2.46 mmol) of1-cyano-2-(3-fluorophenyl)methylcarbonyl-5,6,7-trimethoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of this Example) the title compound was preparedin 49% yield (0.45 g); MS DCl--NH₃ M/Z: 372 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ1.33-1.6 (2H, m), 1.82-1.95 (1H, m), 2.6-3.0 (7H, m), 3.13-3.28 (1H,m), 3.52-3.62 (1H, m), 3.8 (3H, s), 3.82 (3H, s), 3.85 (3H, s), 6.28(1H, s), 6.82-7.1 (3H, m), 7.2-7.3 (1H, m).

Step 4:trans-3-(3-Fluorophenyl)-methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7,8-trimethoxy-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 7, replacing the productof Example 6 with 0.8 g (2.16 mmol) of the product of Step 4 of thisExample, the title compound was prepared in 60% yield (0.53 g), m.p.241°-242° C.; MS DCl--NH₃ M/Z: 386 (M+H)⁺. Analysis calculated for C₂₃H₂₉ ClFNO₃ +0.5H₂ O: C, 64.10; H, 7.02; N, 3.25. Found: C, 64.49; H,6.83; N, 3.21.

EXAMPLE 413-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7,9-trimethoxy-1H-benz[e]isoindolehydrochloride Step 1:1-Cyano-2-[1-(13-dithiane)-2-(3-fluorophenyl)ethyl]-5,6,8-trimethoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 3 of Example 1, replacing1-cyano-6-methoxy-3,4-dihydronaphthalene with 8.3 g (33.9 mmol) of1-cyano-5,6,8-trimethoxy-3,4-dihydronaphthalene (prepared as describedby F. Z. Basha, et al. in J. Organic Chemistry, 50: 4160-2 (1985)), thetitle compound was prepared in 27% yield (4.4 g); MS DCl--NH₃ M/Z 474(M+H)⁺, ¹ H NMR (CDCl₃) δ1.7-2.1 (3H, m), 2.38-2.8 (7H, m), 2.88-3.28(3H, m), 3.78 (3H, s), 3.88 (3H, s), 3.92 (3H, s), 4.57-4.63 (1H, m),6.42 (1H, s), 6.9-7.12 (1H, m), 7.13-7.3 (3H, m).

Step 2:1-Cyano-2-(3-fluorophenyl)methylcarbonyl-5,6,8-trimethoxy-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 1 of Example 6, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 4.4 g (9.3 mmol) of1-cyano-2-[1-(13-dithiane)-2-(3-fluorophenyl)ethyl]-5,6,8-trimethoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 1 of this Example), the title compound was preparedin 61% yield (2.3 g), m.p. 58°-62° C.; MS DCl--NH₃ M/Z: 401 (M+NH₄)⁺ ; ¹H NMR (CDCl₃) δ1.95-2.12 (1H, m), 2.33-3.48 (1H, m), 2.33-2.48 (1H, m),2.6-2.8 (2H, m), 3.08-3.2 (1H, m), 3.75 (3H, s), 3.88 (6H, s), 3.93 (2H,d, J=1.5 Hz), 4.38 (1H, dd, J=1.5 Hz, 4.5 Hz), 6.4 (1H, s), 6.93-7.2(3H, m), 7.28-7.38 (1H, m).

Step 3:3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6,7,9-trimethoxy-1H-benz[e]isoindolehydrochloride

Following the procedures described in Step 2 of Example 6, replacing1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalenewith 2.3 g (6 mmol) of1-cyano-2-(3-fluorophenyl)methylcarbonyl-5,6,8-trimethoxy-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of this Example) the title compound was preparedin 55% yield (1.25 g) as the free amine and then converted to thehydrochloride salt, m.p. 135°-138° C.; MS DCl--NH₃ M/Z: 372 (M+H)⁺.Analysis calculated for C₂₂ H₂₆ ClFNO₃ +H₂ O: C, 62.19; H, 6.59; N,3.30. Found: C, 62.29; H, 6.93; N, 3.21.

Step 4:3-(3-Fluorophenyl)-methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6,7,9-trimethoxy-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 7, replacing the productof Example 6 with 0.52 g (1.36 mmol) of the product of Step 3 of thisExample, the title compound was prepared in 58% yield (0.3 g), m.p.195°-200° C.; MS DCl--NH₃ M/Z: 386 (M+H)⁺. Analysis calculated for C₂₃H₂₉ ClFNO₃ +1.5H₂ O: C, 61.53; H, 7.18; N, 3.12. Found: C, 61.91; H,6.66; N, 3.06.

EXAMPLE 426,7-Dimethoxy-9-fluoro-3-(3-fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindolehydrochloride Step 1: 1-Cyano-5,6-dimethoxy-3,4-dihydronaphthalene

Following the procedures described in Step 2 of Example 1, replacing6-methoxy-α-tetralone with 5,6-dimethoxy-8-fluoro-α-tetralone, the titlecompound was prepared. 5,6-Dimethoxy-8-fluoro-α-tetralone was preparedas described by J. F. DeBernardis and F. Z. Basha in Example Number 62through Example Number 67 in U.S. Pat. No. 4,634,705, (issued Jan. 6,1987).

Step 2:1-Cyano-5,6-dimethoxy-2-[1-(1,3-dithiane)-2-(3-fluorophenyl)ethyl]-8-fluoro-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 3 of Example 1, replacing1-cyano-6-methoxy-3,4-dihydronaphthalene with 13.4 g (57.5 mmol) of1-cyano-8-fluoro-5,6-dimethoxy-3,4-dihydronaphthalene (the product ofStep 1 of this Example), and replacing 2-phenylmethyl-1,3-dithiane with15.73 g (69 mmol) of 2-(3-fluorophenyl)methyl-1,3-dithiane (the productof Step 1 of Example 15), the title compound was prepared in 18% yield;MS DCl--NH₃ M/Z: 462 (M+H)⁺ ; ¹ H NMR (CDCl₃) d 172-2.12 (3H, m),2.4-3.04 (7H, m), 3.07, 3.74 (2H, dd, J=15 Hz), 3.17-3.2 (1H, m), 3.8(3H, s), 3.85 (3H, s), 4.6 (1H, dd. J=4.5 Hz, 1.5 Hz), 6.6 (1H, t, J=9Hz), 6.9-7.3 (4H, m).

Step 3:1-Cyano-5,6-dimethoxy-8-fluoro-2-(3-fluorophenyl)methylcarbonyl-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 1 of Example 6, replacing1-cyano-2-[1-(13-dithiane)-2-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphthalenewith 5.5 g (11.8 mmol) of1-cyano-5,6-dimethoxy-2-[1-(13-dithiane)-2-(3-fluorophenyl)ethyl]-8-fluoro-1,2,3,4-tetrahydronaphthalene(the product of Step 2 of this Example), the title compound was preparedin 36% yield (1.36 g); MS DCl--NH₃ M/Z: 389 (M+NH₄)⁺.

Step 4:6,7-Dimethoxy-9-fluoro-3-(3-fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindole

Following the procedures described in Step 2 of Example 6, replacing1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalenewith 1.36 g (3.67 mmol) of1-cyano-5,6-dimethoxy-8-fluoro-2-(3-fluorophenyl)methylcarbonyl-1,2,3,4-tetrahydronaphthalene(the product of Step 3 of this Example) the title compound was preparedin 30% yield (0.42 g); MS DCl--NH₃ M/Z: 360 (M+H)⁺.

Step 5:6,7-Dimethoxy-9-fluoro-3-(3-fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 7, replacing the productof Example 6 with 0.39 g (1.09 mmol) of the product of Step 4 of thisExample, the title compound was prepared; MS DCl--NH₃ M/Z: 374 (M+H)⁺.Analysis calculated for C₂₂ H₂₆ ClF₂ NO₂ : C, 64.46; H, 6.39; N, 3.42.Found: C, 64.01; H, 6.51; N, 3.36.

EXAMPLE 43cis-7-Bromo-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt Step 1:7-Bromo-1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene

To a solution of 10.2 g (42.3 mmol) of 2-phenylmethyl-1,3-dithiane (fromStep 1 of Example 1) in 100 mL of anhydrous THF at 0° C. under nitrogenatmosphere, was added 17 mL of a 1.5M solution of n-butyl lithium (42.3mmol) in hexane. The reaction mixture was stirred for approximately 1 hand 15 min at 0° C. and then was cooled to -78° C. The solution of2-benzyl-2-lithio-1,3-dithiane was then added, dropwise over a 15 minperiod, to a solution of 9 g (38.4 mmol) of6-bromo-1-cyano-3,4-dihydronaphthalene (prepared as described by F. Z.Basha, et al. in J Organic Chemistry, 50: 4160-2 (1985)) in 100 mL ofTHF, at -78° C. The reaction mixture was allowed to warm to ambienttemperature, was stirred at ambient temperature, under nitrogen for 2.5h, and then was cooled to -78° C. and quenched by the addition of 50 mLof saturated aqueous ammonium chloride solution. The layers wereseparated and the aqueous layer extracted with two portions of ethylacetate. The combined organic layer was washed with brine, dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresultant oil was triturated with diethyl ether/hexane and the solidpurified by chromatography on silica gel eluted with 8:1 hexane:ethylacetate to afford 15.46 g (90% yield) of the compound; MS DCl--NH₃ M/Z:444, 446(M+H)⁺ ;¹ H NMR (CDCl₃) δ1.62-1.99 (2H, m), 2.05-2.19 (1H, m),2.49-3.18 (9H, m), 3.71 (1H, d), 4.38-4.48 (1H, m), 7.07-7.45 (8H, m).

Step 2:1-Aminomethyl-6-bromo-2-[1-(1,3-dithiane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene

6-Bromo-1-cyano-2-[1-(1,3-dithiane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene1 g (2.25 mmol), from Step 1, was dissolved in 10 mL of anhydrous THF.To the resultant solution at ambient temperature, was added 2.3 mL (2.3mmol, 1 equivalent) of a 1.0M solution of borane in THF and the reactionmixture was heated at reflux temperature for 5 h. The reaction mixturewas concentrated in vacuo and the residue was dissolved in methanol.Methanol saturated with anhydrous hydrogen chloride was added and thereaction mixture heated at reflux temperature overnight. The solvent wasremoved under reduced pressure and the residue partitioned between 15%potassium hydroxide and methylene chloride (1:4). The resultant layerswere separated and the aqueous layer was extracted with two portions ofmethylene chloride. The combined methylene chloride extracts were driedover anhydrous magnesium sulfate, filtered and adsorbed onto silica gel.The silica gel was loaded on a silica gel column and eluted with ethylacetate:formic acid:water (25:1:1 v/v/v) to give 650 mg (64% yield) ofthe desired product as the formic acid salt; MS DCl--NH₃ M/Z: 448, 450(M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.84-2.32 (5H, m), 2.68-3.02 (6H, m),3.29-3.51 (3H, m), 3.47 (1H, d), 3.94 (1H, d), 6.96 (1H, d), 7.15-7.33(7H, m).

Step 3:1-(N-Acetyl)aminomethyl-6-bromo-2-[1-(1,3-dithiane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene

1-Aminomethyl-6-bromo-2-[1-(1,3-dithiane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene(6.15 g (13.7 mmol) from Step 2 was dissolved in 20 mL of pyridine andacetic anhydride (1.9 mL, 20.6 mmol) was added to the resultantsolution, under a nitrogen atmosphere. The reaction mixture was heatedfor approximately 1 h at 50° C. The reaction mixture was allowed to coolto ambient temperature and it was stirred at ambient temperature for 0.5h and then poured on to a slurry of ice and concentrated hydrochloricacid. The resultant aqueous mixture was extracted with three portions ofmethylene chloride and the combined organic layers were dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to give5.73 g (85% yield) of the title compound; MS DCl--NH₃ M/Z: 490, 492(M+H)⁺.

Step 4:1-(N-Acetyl)aminomethyl-6-bromo-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalene

N-Bromosuccinimide (NBS; 16.6 g (93.5 mmol) was dissolved in 500 mL of97:3 acetone:water and the resultant mixture was cooled to 0° C.1-(N-acetyl)aminomethyl-6-bromo-2-[1-(1,3-dithiane)-2-phenylethyl]-1,2,3,4-tetrahydronaphthalene(5.73 g, 11.68 mmol) from Step 3 was dissolved in 100 mL of 97:3acetone:water and the resultant solution was added to the NBS solutionover a 10 min period. The reaction mixture was stirred at 0° C. for 10min and then poured onto a slurry of ice and sodium sulfite. Theresultant phases were separated. The organic layer was concentratedunder reduced pressure and the residue dissolved in water. The solidphase was dissolved in water and combined with the aqueous solution ofthe residue from the organic phase. The combined aqueous solution wasextracted with three portions of methylene chloride. The combinedorganic extracts were dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure to afford the title compound,which was carried on to the next step without purification; MS DCl--NH₃M/Z: 400, 402 (M+H)⁺, 417, 419 (M+NH₄)⁺.

Step 5:cis-7-Bromo-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

1-(N-Acetyl)-aminomethyl-6-bromo-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalenefrom Step 4 was dissolved in 100 mL of THF and 200 mL of 6N aqueoushydrochloric acid solution was added to the resultant solution. Thereaction mixture was heated at reflux temperature overnight and thenconcentrated under reduced pressure to 30 mL, The aqueous concentratewas dissolved in 300 mL of methanol and 2.14 g (34 mmol) of sodiumcyanoborohydride in 50 mL of methanol was added, dropwise, over a 10minute period. The reaction mixture was stirred at ambient temperaturefor 1 h and then concentrated in vacuo. The residue was dissolved inwater and the solution was made basic by the addition of concentratedaqueous sodium hydroxide solution. The aqueous solution was extractedwith three portions of methylene chloride and the combined organiclayers were dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The concentrated solution was adsorbed ontosilica gel. The dried silica gel was loaded onto a silica gel column andeluted with ethyl acetate:formic acid:water (18:1:1) to give 1.7 g (40%yield) of the formic acid salt of the desired product. The formic acidsalt was converted to the methanesulfonic acid salt via the free amineto give the title compound, m.p. 134.5°-135° C.; MS DCl--NH₃ M/Z: 442,444 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.42-1.60 (1H, m), 2.02-2.13 (1H, m),2.56-2.71 (1H, m), 2.68 (3H, m), 2.71-2.88 (1H, m), 2.88-3.10 (4H, m),3.24 (1H, dd), 3.60-3.80 (2H, m), 4.10-4.20 (1H, m), 7.06 (1H, d),7.27-7.44 (7H, m). Analysis calculated for C₂₀ H₂₄ BrNO₃ S: C, 54.80; H,5.52; N, 3.20. Found: C, 54.54; H, 5.49; N, 3.14.

EXAMPLE 44cis-7-Bromo-2,3,3a,4,5,9b-hexahydro-2-methyl-3-phenylmethyl-1H-benz[e]isoindolemethanesulfonic acid salt

Ethyl formate (8 mL) was added to a solution of7-bromo-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-1H-benz[e]isoindole, fromExample 43, in 30 mL of toluene. The reaction mixture was heated atreflux temperature under a nitrogen atmosphere for 3 h. The solvent andexcess ethyl formate were evaporated in vacuo and the residue wasdissolved in 30 mL of dry THF under a nitrogen atmosphere. Borane (5 mLof a 1.00M solution in THF) was added and the reaction mixture washeated at reflux temperature for 1.5 h. Methanol saturated withanhydrous hydrogen chloride was added to the reaction mixture and thereflux was continued for 5 h. The reaction mixture was then allowed tocool to ambient temperature and was stirred at ambient temperature forapproximately 64 h. The solvents were removed in vacuo and the residuewas made basic by the addition of 1N aqueous sodium hydroxide solutionand the resultant aqueous mixture was extracted with three portions ofmethylene chloride. The combined organic extract was dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified on silica gel eluted with ethylacetate:water:formic acid (18:1:1 v/v/v) to give 630 mg (76% yield) ofthe title compound; MS DCl--NH₃ M/Z: 356, 358 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ1.81-2.01 (2H, m), 2.45-2.57 (1H, m), 2.61-2.74 (1H, m), 2.80 (3H, s),2.83, 2.85 (2 s, N--CH₃), 2.88-2.97 (1H, m), 3.19-3.39 (3H, m),3.51-3.72 (3H, m), 3.92-4.04 (1H, m), 6.86 (1H, d), 7.23-7.41 (7H, m).Analysis calculated for C₂₁ H₂₆ BrNO₃ S: C, 55.75; H, 5.79; N, 3.10.Found: C, 55.51; H, 5.86; N, 3.04.

EXAMPLE 45cis-3-(2-Chloro-5-N-ethyl-N-methylaminophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindolehydrochloride Step 1: 2-(3-Nitrophenyl)-1-nitro-2-ethene

A mixture of 30.22 g (200 mmol) of 3-nitrobenzaldehyde, 14 g of ammoniumacetate and 25 mL of nitromethane in 230 mL of glacial acetic acid washeated at reflux temperature for 3 h and then poured onto ice. Theresultant aqueous mixture was made basic by the addition of 45% aqueouspotassium hydroxide solution. The precipitate was filtered andcrystallized from ethyl acetate/hexane to give 14 g (43% yield) of thetitle compound; MS DCl--NH₃ M/Z: 165 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ7.7 (2H,dd, J=15 Hz), 7.88 (1H, d), 8.06 (1H, d), 8.37 (1H, d, J=15 Hz), 8.42(1H, d).

Step 2: 2-(3-Nitrophenyl)-1-nitroethane

A solution of 14 g (72 mmol) of 2-(3-nitrophenyl)-1-nitro-2-ethene, fromStep 1, in 200 mL of dioxane was added dropwise to a stirred suspensionof 6 g (157 mmol) of sodium borohydride in a mixture of 140 mL ofdioxane and 60 mL of ethanol. The reaction mixture was stirred atambient temperature for 2 h. The excess sodium borohydride was destroyedwith acid. The reaction mixture was concentrated in vacuo and theresidue was partitioned between methylene chloride and water (4:1). Theorganic layer was dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified on silica gel eluted with 20%methylene chloride in hexane to afford 6.5 g (45.8% yield) of the titlecompound; MS DCl--NH₃ M/Z: 214 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ3.45 (2H, t,J=7.5 Hz), 4.7 (2H, t, J=7.5 Hz), 7.5-7.58 (2H, m), 8.11-8.18 (2H, m).

Step 3:1-(1-Carbomethoxy-1,2,3,4-tetrahydro-2-naphthyl)-2-(3-nitrophenyl)-1-nitroethane

To a mixture of 2 g (10.6 mmol) of1-carbomethoxy-3,4-dihydronaphthalene, from Step 1 of Example 46, and2.08 g (10.6 mmol) of 2-(3-nitrophenyl)-1-nitroethane, from Step 2, in 1mL of acetonitrile was added 0.2 mL of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction mixture wasstirred at ambient temperature for 0.5 h and then diluted with ethylacetate. The reaction mixture was washed with 2N aqueous hydrochloricacid solution. The organic layer was separated, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to give 3.96 g(97% yield) of the title compound as a mixture of diastereomers whichwas taken on without purification to the next step; MS DCl--NH₃ M/Z: 402(M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ1.52-1.86 (1H, m), 2.1-2.35 (1H, m),2.42-2.65 (1H, m), 2.78-3.15 (2H, m), 3.2-3.33 (1H, m), 3.38-3.55 (1H,m), 3.78-3.81 (3H, s), 3.91-4.18 (1H, m), 4.68-4.88 (1H, m), 7.12-7.42(4H, m), 7.48-7.58 (2H, m), 8.01-8.18 (2H, m).

Step 4:3-(3-Acetaminophenyl)methyl-2,3,3a4,5,9b-hexahydro-1H-oxo-benz[e]isoindole

A mixture of 3.96 g (10.6 mmol) of1-(1-carbomethoxy-1,2,3,4-tetrahydro-2-naphthyl)-2-(3-nitrophenyl)-1-nitroethane,from Step 3, and 12 g of zinc in 400 mL of glacial acetic acid washeated at reflux temperature overnight. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between ethylacetate and water (4:1). The ethyl acetate solution was dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel eluted with 90%hexane in ethyl acetate to afford 2.36 g (70% yield) of the titlecompound as a mixture of isomers; MS DCl--NH₃ M/Z:335 (M+H)⁺,352(M+NH₄)⁺.

Step 5:3-(5-Acetamino-2-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-oxo-benz[e]isoindole

To a suspension of 2.0 g (6 mmol) of3-(3-acetaminophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-oxo-benz[e]isoindole,from Step 4, in 20 mL of chloroform, cooled to -45° C., was added 0.75mL of t-butylhypochlorite. The reaction mixture was stirred at -45° C.for 2 h, and at 0° C. for 1 h. The reaction mixture was poured intowater and the resultant aqueous mixture was extracted with methylenechloride. The organic layer was dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to afford 1.9 g (86% yield) of thetitle compound as a mixture of diastereomers; MS DCl--NH₃ M/Z:369(M+H)⁺,386 (M+NH₄)⁺.

Step 6:3-(5-(N-Ethyl)amino-2-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-oxo-benz[e]isoindole

3-(5-Acetamino-2-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-oxo-benz[e]isoindole(2.4 g, 6.5 mmol), from Step 5, was dissolved in 150 mL of anhydrousTHF. To the resultant solution was added 35 mL of a 1M solution ofborane in THF (35 mmol). The reaction mixture was heated at refluxtemperature for 4 h. The solvent was removed in vacuo and the residuewas partitioned between methylene chloride and dilute aqueous sodiumhydroxide solution. The organic layer was separated, dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel eluted with ethylacetate:formic acid:water (18:1:1) to give 0.8 g (36% yield) of thetitle compound; MS DCl--NH₃ M/Z: 348 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.12-1.45(3H, m), 1.5-1.8 (1H, m), 1.88-1.98 (1H, m), 2.1-2.4 (1H, m), 2.5-2.9(3H, m), 3.02-3.25 (2.5H, m), 3.45-3.51 (1.5H, m), 3.63-3.72 (0.5H, m),3.78-3.88 (0.5H, m), 6.44-6.51 (1H, m), 6.52-6.6 (1H, dd), 6.95-7.18(5H, m).

Step 7:cis-3-(3-Chloro-4-N-ethyl-N-methylaminophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindolehydrochloride

To 0.8 g (2.35 mmol) of3-(5-(N-ethyl)amino-2-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-oxo-benz[e]isoindole,from Step 6, was added 25 mL of methanol, 6 mL of formalin (37% aqueousformaldehyde solution) and 0.5 g of sodium cyanoborohydride. Thereaction mixture was stirred at ambient temperature for 0.5 h and thenconcentrated in vacuo. The residue was partitioned between methylenechloride and dilute aqueous sodium hydroxide solution. The organic layerwas separated, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel eluted with 2:1 diethyl ether:hexane saturated with ammoniumhydroxide to give the free amine of the desired product as the majorisomer. The amine was converted to the hydrochloride salt which wasrecrystallized from acetone/diethyl ether to give 0.22 g (25.5% yield)of the title compound, m.p. 145°-148° C.; MS DCl--NH₃ M/Z: 369 (M+H)⁺ ;¹ H NMR (CDCl₃) δ1.12 (3H, t), 1.65-1.72 (1H, m), 2.05-2.12 (1H, m),2.2-2.3 (1H, m), 2.48 (3H, s), 2.59-2.72 (1H, m), 2.8 (3H, s), 2.78-3.1(5H, m), 3.15-3.28 (1H, m), 3.3-3.48 (3H, m), 6.52 (1H, dd), 6.7 (1H,bs), 7.0-7.15 (4H, m), 7.18 (1H, d).

EXAMPLE 463-(3-Chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindoleStep 1: 1-Carbomethoxy-3,4-dihydronaphthalene

1-Cyano-3,4-dihydronaphthalene (1 g, 6.45 mmol), the product of Step 1of Example 9, was added to 10 mL of a 77% solution of concentratedsulfuric acid in methanol. The reaction mixture was heated at 95° C. for2 h and then poured onto ice. The aqueous mixture was filtered and thefiltrate was extracted with three portions of ethyl acetate. Thecombined organic extract was washed with brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified on silica gel eluted with 20% ethyl acetate in hexane to afford0.54 g (45% yield) of the title compound as a colorless oil; MS DCl--NH₃M/Z: 189 (M+H)⁺, 206 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ2.37-2.45 (2H, m),2.73-2.82 (2H, t, J=7.5 Hz), 3.85 (3H, s), 7.13-7.25 (4H, m), 7.78 (1H,d, J=7.5 Hz).

Step 2: 2-(3-Chlorophenyl)-1-nitroethene

A mixture of 28.11 g (200 mmol) of 3-chlorobenzaldehyde, 15.4 g ofammonium acetate and 32.5 mL of nitromethane in 230 mL of glacial aceticacid was heated at reflux temperature for 3 h and then poured onto ice.The resultant aqueous mixture was made basic by the addition of 45%aqueous potassium hydroxide. The precipitate was filtered andcrystallized from ethyl acetate/hexane to give 5 g of the titlecompound. The filtrate was concentrated to afford an additional 13.5 gof product.

Step 3: 2-(3-Chlorophenyl)-1-nitroethane

A solution of 13.5 g (72 mmol) of 2-(3-Chlorophenyl)-1-nitroethene, fromStep 2, in 200 mL of dioxane was added dropwise to a stirred suspensionof 6 g (157 mmol) of sodium borohydride in a mixture of 140 mL ofdioxane and 60 mL of ethanol. The reaction mixture was stirred atambient temperature for 2 h and then the excess borohydride was quenchedwith acid. The reaction mixture was concentrated in vacuo and theresidue was partitioned between methylene chloride and water (4:1). Theorganic layer was dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified on silicagel eluted with 20% methylene chloride in hexane to afford 6.3 g (48%yield) of the title compound; MS DCl--NH₃ M/Z: 203 (M+NH₄)⁺ ; ¹ H NMR(CDCl₃) δ3.3 (2H, t, J=7.5 Hz), 4.6 (2H, t, J= 7.5 Hz), 7.05-7.3 (4H,m).

Step 4:1-(1-Carbomethoxy-1,2,3,4-tetrahydro-2-naphthyl)-2-(3-chlorophenyl)-1-nitroethane

To a mixture of 0.47 g (2.5 mmol) of1-carbomethoxy-3,4-dihydronaphthalene, from Step 1, and 0.45 g (2.5mmol) of 2-(3-chlorophenyl)-1-nitroethane, from Step 3, was added 180 μL(1.25 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 5 mL ofacetonitrile. The reaction mixture was stirred at ambient temperaturefor 45 min and then diluted with methylene chloride. The resultantmixture was poured into 2N aqueous hydrochloric acid solution and thelayers were separated. The organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to give 1.1 g ofoil. The oil was purified by chromatography on silica gel eluted with10% ethyl acetate in hexane to give isomeric products. The titlecompound was obtained in 45% yield (0.17 g); MS DCl--NH₃ M/Z: 391 (M+H)⁺; ¹ H NMR (CDCl₃) δ1.48-1.52 (1H, m), 2.1-2.2 (1H, m), 2.71-3.22 (6H,m), 3.75 (3H, s), 4.65-4.75 (1H, m), 6.97-7.28 (8H, m).

Step 5:3-(3-Chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-oxo-benz[e]isoindole

A mixture of 3.1 g (8.3 mmol) of1-(1-carbomethoxy-1,2,3,4-tetrahydro-2-naphthyl)-2-(3-chlorophenyl)-1-nitroethane,from Step 4, and 6 g of zinc in 350 mL of acetic acid was heated atreflux temperature overnight. The reaction mixture was concentrated invacuo and the residue was partitioned between ethyl acetate and water(4:1). The ethyl acetate solution was dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel eluted with 80% ethyl acetate in hexane,followed by 100% ethyl acetate to afford 1.8 g (69% yield) of the titlecompound as a mixture of isomers; MS DCl--NH₃ M/Z: 312 (M+H)⁺, 329(M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ1.63-1.81 (1H, m), 1.78-2.02 (1, m),2.63-2.85 (3H, m), 2.87-2.98 (1H, m), 3.52-3.6 (0.5H, m), 3.6-3.72 (1H,m), 4.02-4.11 (0.5H, m), 5.39 (0.5H, bs), 5.58 (0.5H, bs), 7.03-30 (7H,m), 7.49 (0.5H, d), 7.58 (0.5H, d).

Step 6:3-(3-Chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindole

3-(3-Chlorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-oxo-benz[e]isoindole (1.8g, 5.8 mmol), from Step 5, was dissolved in 100 mL of anhydrous THF andto this solution was added 25 mL of a 1M solution of borane in THF (25mmol). The reaction mixture was heated at reflux temperature for 4 h,and then concentrated in vacuo. The residue was dissolved in methylenechloride saturated with hydrogen chloride and the resultant solution washeated at reflux temperature for 4 h. The solvent was removed in vacuoand the residue partitioned between methylene chloride and diluteaqueous sodium hydroxide. The organic layer was separated, dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel eluted with ethylacetate:formic acid:water (18:1:1) to give 0.9 g (53% yield) of thetitle compound; MS DCl--NH₃ M/Z: 298 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.49-1.95(1H, m), 2.11-2.32 (1H, m), 2.6-3.15 (5H, m), 3.32-3.71 (3H, m),7.01-7.3 (8H, m).

EXAMPLE 473-(3-Chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindolehydrochloride

To 0.9 g (3 mmol) of3-(3-chlorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindole, theproduct of Example 46, was added 25 mL of methanol, 5.5 mL of formalin(37% aqueous formaldehyde solution) and 0.5 g of sodiumcyanoborohydride. The reaction mixture was stirred at ambienttemperature for 2 h, acidified with a few drops of methanol saturatedwith hydrogen chloride and then stirred at ambient temperature foranother hour. The reaction was quenched with 6N aqueous hydrochloricacid. The reaction mixture was stirred at ambient temperature for 0.5 hand then concentrated in vacuo. The residue was partitioned betweenmethylene chloride and dilute aqueous sodium hydroxide solution. Theorganic layer was separated, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel eluted with 1:1 diethyl ether:hexanesaturated with ammonium hydroxide to give the free amines of the desiredisomeric products. The amines were converted to the hydrochloride saltswhich were recrystallized from ethyl acetate/diethyl ether to give twoisomeric products. Isomer 1 (0.35 g), m.p. 180°-181° C.; MS DCl--NH₃M/Z: 312 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.6-1.7 (1H, m), 1.84-1.96 (1H, m),2.12-2.23 (1H, m), 2.39 (3H, s), 2.51-2.86 (4H, m), 2.87-2.97 (2H, m),3.16-3.23 (1H, m), 3.29-3.39 (1H, m), 7.01-7.29 (8H, m). Analysiscalculated for C₂₀ H₂₃ Cl₂ N: C, 67.23; H, 6.77; N, 3.92. Found: C,67.42; H, 6.61; N, 3.87. Isomer 2 (0.28 g), m.p. 170°-175° C.; MSDCl--NH₃ M/Z: 312 (M+H)⁺ ; ¹ H NMR (CDCL₃) δ1.18-1.41 (2H, m), 2.17-2.41(3H, m), 2.38 (3H, s), 2.48-2.53 (3H, m), 2.98-3.08 (1H, dd), 3.32-3.48(2H, m), 7.0-7.3 (8H, m). Analysis calculated for C₂₀ H₂₃ Cl₂ N: C,67.23; H, 6.77; N, 3.92. Found: C, 67.26; H, 6.60; N, 3.86.

EXAMPLE 48trans-7-Chloro-3-(3-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindolehydrochloride Step 1: 1-Carbomethoxy-6-chloro-3,4-dihydronaphthalene

6-Chloro-1-cyano-3,4-dihydronaphthalene (5 g, 263 mmol), lit ref, wasdissolved in 77% sulfuric acid in methanol and the resulting solutionwas heated at 95°-100° C. for 2.5 h. The reaction mixture was allowed tocool to ambient temperature and 45 mL was added, followed by 5 mL ofwater. The reaction mixture was stirred at ambient temperature for 2days and then concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and water. The organic layer wasconcentrated in vacuo. The residue was purified by chromatography onsilica gel eluted with 20% ethyl acetate in hexane to give 1.53 g (26%yield) of the title compound; MS DCl--NH₃ M/Z: 240 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ2.37-2.45 (2H, m), 2.75 (2H, t, J=7.5 Hz), 3.85 (3H, s), 7.15(1H, d, J=1.5 Hz), 7.15 (1H, d, 9 Hz), 7.2 (1H, d, J=7.5 Hz), 7.77 (1H,d, J=7.5).

Step 2:1-(1-Carbomethoxy-6-chloro-1,2,3,4-tetrahydro-2-naphthyl)-2-(3-chlorophenyl)-1-nitroethane

Following the procedures described in Step 4 of Example 46, replacing1-carbomethoxy-3,4-dihydronaphthalene with 1.51 g (6.78 mmol) of1-carbomethoxy-6-chloro-3,4-dihydronaphthalene from Step 1, the titlecompound was prepared in 80% yield (2.3 g) as a mixture ofdiastereomers; MS DCl--NH₃ M/Z: 425 (M+H)⁺.

Step 3:7-Chloro-3-(3-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-oxo-benz[e]isoindole

Following the procedures described in Step 5 of Example 46, replacing1-(1-carbomethoxy-1,2,3,4-tetrahydro-2-naphthyl)-2-(3-chlorophenyl)-1-nitroethanewith 0.83 g (1.96 mmol) of1-(1-carbomethoxy-6-chloro-1,2,3,4-tetrahydro-2-naphthyl)-2-(3-chlorophenyl)-1-nitroethane,from Step 2, to give 0.59 g (87% yield) of the title compound as whitecrystals, m.p. 190°-192° C.; MS DCl--NH₃ M/Z: 346 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ1.52-2.05 (2H, m), 2.67-3.0 (5H, m), 3.5-3.6 (1H, m), 4.0-4.1(1H, m), 7.05-7.45 (7H, m).

Step 4:7-Chloro-3-(3-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindole

Following the procedures described in Step 6 of Example 46, replacing3-(3-Chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-oxo-benz[e]isoindolewith 1.25 g (3.62 mmol) of7chloro-3-(3-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-oxo-benz[e]isoindole,from Step 3, the title compound was prepared; MS DCl--NH₃ M/Z: 334(M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.43-1.95 (2H, m), 2.07-2.43 (1H, m),2.54-3.15 (5H, m), 3.2-3.7 (3H, m), 6.92-7.32 (7H, m).

Step 5:trans-6-Chloro-3-(3-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindolehydrochloride

Following the procedures described in Example 44, replacing7-bromo-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-1H-benz[e]isoindole with1.35 g (4.05 mmol)7-chloro-3-(3-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-1H-benz[e]isoindole,from Step 4, the title compound was prepared as a mixture with Example49. The two diastereomers were separated by chromatography on silica geleluted with 2:1 diethyl ether: hexane saturated with ammonium hydroxide.Example 48 was obtained in 40% yield (0.56 g), m.p. 160°-162° C.; MSDCl--NH₃ M/Z: 346 (M+H)⁺. Analysis calculated for C₂₀ H₂₂ Cl₃ N+H₂ O: C,59.94; H, 6.04; N, 3.49. Found: C, 60.46; H, 5.72; N, 3.49.

EXAMPLE 49cis-7-Chloro-3-(3-chlorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-1H-benz[e]isoindolehydrochloride

The title compound was obtained as described in Example 48 in 33% yield(0.46 g), m.p. 110°-112° C.; MS DCl--NH₃ M/Z: 346 (M+H)⁺. Analysiscalculated for C₂₀ H₂₂ Cl₃ N+H₂ O: C, 59.94; H, 6.04; N, 3.49. Found: C,59.63; H, 5.87; N, 3.46.

EXAMPLE 501,2,3,4,4a,5,6,10b-Octahydro-4-phenylmethyl-benz[f]isoquinolinemethanesulfonic acid salt Step 1:1-Cyano-2-(1-cyano-2-phenyl-1-ethyl)-1,2,3,4-tetrahydronaphthalene

To a solution of 3.5 mL (25 mmol) of diisopropylamine in 40 mL of THF at-78° C., under a nitrogen atmosphere, was added n-butyllithium (9.5 mLof a 2.5M solution in THF, 23.7 mmol) and the resultant solution wasstirred at -78° C. for 0.5 h. To the stirred solution was slowly added asolution of 2.75 g (21 mmol) of 3-phenylpropiononitrile in 40 mL of THF.The reaction mixture was stirred for 45 min at -78° C. and then asolution of 3.1 g (20 mmol) of 1-cyano-3,4-dihydronaphthalene (theproduct of Step 1 of Example 9) in 40 mL of THF was added. The reactionmixture was stirred at -78° C. for 0.5 h and then the reaction wasquenched by pouring the reaction mixture into saturated aqueous ammoniumchloride solution. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo togive 5.70 g (quantitative yield) of the title compound as a mixture ofthree diastereomers; MS DCl--NH₃ M/Z: 287 (M+H)⁺.

Step 2:1,3-Dioxo-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline

1-Cyano-2-(1-cyano-2-phenyl-1-ethyl)-1,2,3,4-tetrahydronaphthalene (9.43g, 33 mmol), from Step 1, was dissolved in 200 mL of methylene chlorideand the resultant solution was cooled to 0° C. The reaction mixture wasflushed with nitrogen gas and hydrogen bromide gas was then bubbled infor 1.5 h at 0° C. Nitrogen was bubbled through the reaction mixture for1.5 h to remove the excess hydrogen bromide and the reaction mixture wasthen allowed to warm to ambient temperature. The solvent was removedunder reduced pressure and the residue was washed with diethylether/hexane (1:2). The solvent was decanted and the residue wasdissolved in 100 mL of DMF:water (1:1). The resultant solution washeated at reflux for 3 h, allowed to cool to ambient temperature andstirred overnight at ambient temperature. The reaction mixture waspoured into ice water and the aqueous mixture was extracted with ethylacetate. The ethyl acetate extract was washed with water, dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo toafford the title compound.

Step 3: 1,2,3,4,4a,5,6,10b-Octahydro-4-phenylmethyl-benz[f]isoquinolinemethanesulfonic acid salt

To a solution of1,3-Dioxo-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline,from Step 2, in 40 mL of THF was added a solution of borane in THF andthe reaction mixture was heated at reflux for 3 h. The solvent wasremoved in vacuo and the residue was dissolved in 25 mL of methanol. Tothis solution was added 30 mL of methanol saturated with anhydroushydrogen chloride and the reaction mixture was heated at reflux for 2 h.The solvent was evaporated in vacuo and the residue was partitionedbetween methylene chloride and 3 N aqueous sodium hydroxide solution(4:1). The basic aqueous layer was extracted with two portions ofmethylene chloride. The combined methylene chloride layers were driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure to give 0.47 g of the desired product as a mixture ofthe two diastereomers of the free amine which was converted to themethanesulfonic acid salt, m.p. 156°-157° C.; MS DCl--NH₃ M/Z: 278(M+H)⁺. Analysis calculated for C₂₁ H₂₇ NO₃ S: C, 67.53; H, 7.29; N,3.75. Found: C, 67.03; H, 7.24; N, 3.68.

EXAMPLE 51 cis-2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinolinehydrochloride

The product of Example 50 was subjected to reductive methylation asdescribed in Example 2. The two diastereomers of the desired productwere separated by chromatography on silica gel eluted with 2:1 diethylether:hexane saturated with ammonium hydroxide to give the titlecompound and 52 as the free amine products. The free amine of the titlecompound was converted to the hydrochloride salt which wasrecrystallized form a mixture of hexane and ethyl acetate, m.p.204°-205° C.; MS DCl--NH₃ M/Z: 292 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.5-1.6(1H, m), 1.78-1.92 (2H, m), 2.05-2.35 (3H, m), 2.18 (3H, s), 2.64-3.0(5H, m), 3.15-3.25 (1H, m), 7.0-7.28 (9H, m). Analysis calculated forC₂₁ H₂₆ ClNO+0.25H₂ O: C, 75.88; H, 8.04; N, 4.21. Found: C, 75.76; H,7.99; N, 4.17.

EXAMPLE 52trans-2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinolinehydrochloride

The free amine of the title compound, obtained as described in Example51, was converted to the hydrochloride salt which was recrystallizedfrom a mixture of hexane and ethyl acetate, m.p. 233°-234° C.; MSDCl--NH₃ M/Z: 292 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.83-2.18 (3H, m), 2.66-3.22(8H, m), 2.83 (3H, s), 3.37-3.47 (1H, m), 7.1-7.38 (9H, m). Analysiscalculated for C₂₁ H₂₆ ClNO+0.25H₂ O: C, 75.88; H, 8.04; N, 4.21. Found:C, 75.89; H, 8.05; N, 4.15.

EXAMPLE 53 8-Methoxy-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinolinemethanesulfonic acid Step 1:1-Cyano-2-(cyanomethyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene

To a solution of 1.05 mL (7.5 mmol) of diisopropylamine in 10 mL of THFat -78° C., under a nitrogen atmosphere, was added n-butyllithium (2.2mL of a 2.5M solution in THF, 5.5 mmol) and the resultant solution wasstirred at -78° C. for 40 min. To the stirred solution was added,dropwise over a 25 minute period, a solution of 274 μL (5.25 mmol) ofacetonitrile in 5 mL of THF. The solution was stirred for 20 min at -78°C. and then a solution of 926 mg (5 mmol) of1-cyano-6-methoxy-3,4-dihydronaphthalene (the product of Step 2 ofExample 1) in 5 mL of THF was added via syringe pump over a 20 minperiod. The reaction mixture then allowed to warm to ambient temperatureand was stirred at ambient temperature for 1 h and then the reaction wasquenched by pouring the reaction mixture into and then the reaction wasquenched by pouring the reaction mixture into saturated aqueous ammoniumchloride solution. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by chromatography on silica gel eluted with 25%ethyl acetate in hexane to give 840 mg (74% yield) of the title compoundas a 1:1 mixture of the cis and trans isomers; MS DCl--NH₃ M/Z: 244(M+H)⁺.

Step 2:1,3-Dioxo-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline

Following the procedures described in Step 2 of Example 50, replacing1-cyano-2-(1-cyano-2-phenyl-1-ethyl)-1,2,3,4-tetrahydronaphthalene with7.33 g (32.4 mmol) of1-cyano-2-(cyanomethyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene, fromStep 1, the title compound was prepared in 63% yield (5 g) as a 10:1mixture of the cis and trans isomers; MS DCl--NH₃ M/Z: 246 (M+H)⁺, 263(M+NH₄)⁺ ; ¹ H NMR of cis isomer (CDCl₃) δ1.67-1.81 (1H, m), 1.87-1.98(1H, m), 2.52-2.63 (1H, m), 2.67 (1H, dd), 2.83 (1H, dd), 2.89 (2H, m),3.73 (1H, d), 3.80 (3H, s), 6.67 (1H, d), 6.80 (1H, dd), 7.28 (1H, d),7.84 (1H, bs).

Step 3: 8-Methoxy-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinolinemethanesulfonic acid salt

Following the procedures described in Step 3 of Example 50, replacing1,3-dioxo-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline,with 5.0 g (20.4 mmol) of1,3-dioxo-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline,from Step 2, the desired product was obtained as the free amine whichwas purified on silica gel eluted with ethyl acetate:water:formic acid(18:1:1) to give 2.65 g (60% yield) of the methanesulfonic acid salt,m.p. 171°-174° C.; MS DCl--NH₃ M/Z: 218 (M+H)⁺. ¹ H NMR (CDCl₃)δ1.61-1.70 (1H, m), 1.78-1.87 (1H, m), 1.94-2.04 (1H, m), 2.18-2.38 (2H,m), 2.78 (3H, s), 2.83-2.90 (2H, m), 2.92-3.08 (2H, m), 3.25-3.47 (3H,m), 3.77 (3H, s), 6.62 (1H, d), 6.71 (1H, dd), 7.09 (1H, d), 8.34-9.01(1H, bs). Analysis calculated for C₁₅ H₂₃ NO₄ S: C, 57.49; H, 7.40; N,4.47. Found: C, 57.31; H, 7.39; N, 4.36.

EXAMPLE 548-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinolinemethanesulfonic acid

The product of Example 53 was subjected to reductive methylation asdescribed in Example 2. The two diastereomers of the desired product(formed in a ratio of 10:1 cis:trans) were not separated bychromatography. The free amine of the title compound was obtained in 84%yield (670 mg) and converted to the hydrochloride salt, m.p. 107°-114°C.; MS DCl--NH₃ M/Z: 232 (M+H)⁺ 1 H NMR (CDCl₃) δ1.09 (3H, t), 1.47-1.55(1H, m), 1.61-1.76 (2H, m), 1.97-2.17 (4H, m), 2.34-2.48 (2H, m), 2.87(3H, s), 2.97-3.06 (1H, m), 3.77 (3H, s), 6.61 (1H, d), 6.71 (1H, dd),7.06 (1H, d). Analysis calculated for C₁₆ H₂₅ NO₄ S+0.25H₂ O: C, 58.68;H, 7.70; N, 4.28. Found: C, 57.89; H, 7.74; N, 4.42.

EXAMPLE 552-Ethyl-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinolinemethanesulfonic acid

Following the procedures described in Example 3, replacing2,3,3a,4,5,9b-hexahydro-7-methoxy-2-methyl-3-phenylmethyl-1H-benz[e]isoindolewith 1.55 g (7.1 mmol) of the free amine product of Example 53, thetitle compound was prepared, m.p. 141°-141.5° C.; MS DCl--NH₃ M/Z: 246(M+H)⁺. Analysis calculated for C₁₇ H₂₇ NO₄ S: C, 59.80; H, 7.97; N,4.10. Found: C, 59.79; H, 7.94; N, 4.07.

EXAMPLE 562-Ethyl-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinolinemethanesulfonic acid salt Step 1:1-Cyano-2-(1-cyano-2-phenyl-1-ethyl)-1,2,3,4-tetrahydronaphthalene

Following the procedures described in Step 1 of Example 53, replacingacetonitrile with 2.75 g (21 mmol) of 3-phenylpropionitrile, the titlecompound was obtained in 84% yield (5.3 g) as a mixture of isomers; MSDCl--NH₃ M/Z: 334 (M+H)⁺.

Step 2:1,3-Dioxo-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline

Following the procedures described in Step 2 of Example 50, replacing1-cyano-2-(1-cyano-2-phenyl-1-ethyl)-1,2,3,4-tetrahydronaphthalene with6.64 g (21 mmol) of1-cyano-2-(1-cyano-2-phenyl-1-ethyl)-1,2,3,4-tetrahydronaphthalene, fromStep 1, the title compound was prepared and carried on to the next stepwithout purification; MS DCl--NH₃ M/Z: 336 (M+H)⁺, 353 (M+NH₄)⁺.

Step 3:8-Methoxy-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline

Following the procedures described in Step 3 of Example 50, replacing1,3-dioxo-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinolinewith 0.93 g (2.77 mmol) of1,3-dioxo-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline,from Step 2, the desired product was prepared as a mixture of the twodiastereomers.

Step 4:2-Ethyl-8-methoxy-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinolinemethanesulfonic acid salt

Following the procedures described in Example 3, replacing2,3,3a,4,5,9b-hexahydro-7-methoxy-3-phenylmethyl-1H-benz[e]isoindolewith 0.97 g (3.2 mmol) of the product of Step 3, the title compound wasprepared, m.p. 127.5°-134° C.; MS DCl--NH₃ M/Z: 336 (M+H)⁺. ¹ H NMR ofthe free base (CDCl₃) δ1.06 (3H, t), 1.73-2.00 (4H, m), 2.08 (1H, dd),2.27-2.48 (3H, m), 2.56-2.74 (4H, m), 2.78-2.88 (2H, m), 2.92-3.02 (1H,m), 3.77 (3H, s), 6.58 (1H, d), 6.68 (1H, dd), 7.02 (1H, d), 7.13-7.32(5H, m). Analysis calculated for C₂₄ H₃₃ NO₄ S+H₂ O: C, 64.11; H, 7.85;N, 3.12. Found: C, 64.39; H, 7.86; N, 3.07.

EXAMPLE 572,10b-Diethyl-8-ethoxy-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinolinemethanesulfonic acid salt Step 1:1,3-Dioxo-8-hydroxy-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline

To a flask containing 4.69 g (14.8 mmol) of1-cyano-2-(1-cyano-2-phenyl-1-ethyl)-1,2,3,4-tetrahydronaphthalene, theproduct of Step 1 of Example 56, was added 150 mL of glacial acetic acidand 30 mL of concentrated sulfuric acid. The reaction mixture was heatedat 100° C. for 2 h, allowed to cool to ambient temperature and stirredat ambient temperature overnight. Hydrochloric acid (150 mL of a 6Naqueous solution) was added to the reaction mixture and the reactionmixture was heated at reflux for 8 h. The reaction mixture was thenallowed to cool to ambient temperature and was stirred at ambienttemperature for approximately 64 h. The reaction mixture was poured ontoice and the aqueous mixture was made basic by the addition of solidsodium carbonate, followed by saturated aqueous sodium bicarbonatesolution and then 45% aqueous sodium hydroxide solution. The mixture waskept cold (˜0° C.) during the pH adjustment. The aqueous mixture wasextracted with three portions of methylene chloride. The combinedorganic extract was dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel eluted with hexane:ethyl acetate to give1.42 g of the title compound as a mixture of diastereomers; MS DCl--NH₃M/Z: 364 (M+H)⁺, 381 (M+NH₄)⁺.

Step 2:1,3-Dioxo-8-ethoxy-2-ethyl-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline

A solution of 1.42 g (4.42 mmol) of1,3-dioxo-8-hydroxy-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline,from Step 1, in 20 mL of dry DMF was cooled to 0° C. under a nitrogenatmosphere. To this solution at 0° C., was added portionwise, 3 mL of asuspension of sodium hydride in hexane. The reaction mixture was stirredat 0° C. for 10 min and then at ambient temperature for 1 h. Thereaction mixture was cooled back down to 0° C. and 1.24 mL (15.5 mmol)of ethyl iodide was added. The reaction mixture was stirred at 0° C. for0.5 h and at ambient temperature overnight and then concentrated invacuo to give 0.16 g of the title compound; MS DCl--NH₃ M/Z: 406 (M+H)⁺.

Step 3:2,10b-Diethyl-8-ethoxy-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinolinemethanesulfonic acid salt

Following the procedures described in Step 3 of Example 50, replacing1,3-dioxo-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinolinewith 0.93 g (2.77 mmol) of1,3-dioxo-8-methoxy-2-ethyl-1,2,3,4,4a,5,6,10b-octahydro-4-phenylmethyl-benz[f]isoquinoline,from Step 2, the desired product was prepared as a mixture of the twodiastereomers and converted to the methanesulfonic acid salt, m.p.172.5°-173.5° C.; MS DCl--NH₃ M/Z: 378 (M+H)⁺. ¹ H NMR of the free base(CDCl₃) δ0.47 (3H, t), 1.01 (3H, t), 1.39 (3H, t), 1.66-1.96 (4H, m),2.11-2.77 (9H, m), 3.98 (2H, m), 6.54 (1H, d), 6.69 (1H, dd), 7.12 (1H,d), 7.16-7.32 (5H, m).

EXAMPLES 58-70

Following the procedures described in Examples 45-49 starting witheither 1-cyano-5,6-methylenedioxy-3,4-dihydronaphthalene (Examples58-63) or 1-cyano-8-fluoro-5,6-methylenedioxy-3,4-dihydronaphthalene(Examples 64-70) which were prepared as described by F. Z. Basha, et al.in J. Organic Chemistry, 1985, 50: 4160-2, and the appropriatenitromethane derivative as shown in reaction scheme II, Examples 58-70are prepared as disclosed in Table 1.

                  TABLE 1                                                         ______________________________________                                        Example                                                                       Number  Structure                                                             ______________________________________                                        58                                                                                     ##STR19##                                                            59                                                                                     ##STR20##                                                            60                                                                                     ##STR21##                                                            61                                                                                     ##STR22##                                                            62                                                                                     ##STR23##                                                            63                                                                                     ##STR24##                                                            64                                                                                     ##STR25##                                                            65                                                                                     ##STR26##                                                            66                                                                                     ##STR27##                                                            67                                                                                     ##STR28##                                                            68                                                                                     ##STR29##                                                            69                                                                                     ##STR30##                                                            70                                                                                     ##STR31##                                                            ______________________________________                                    

EXAMPLE 71cis-2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinolinStep 1: Ethyl (1-cyano-1,2,3,4-tetrahydronaphthyl-2-yl)acetate

n-Butyl lithium (14.2 mL of a 2.5M solution in hexane, 35.4 mmol) wasadded to a solution of diisopropylamine (6.77 mL, 48 mmol) in 100 mL ofdry THF at -78° C. under a nitrogen atmosphere. The solution was stirredat -78° C. for 15 min and then ethyl acetate (3.3 mL, 33.8 mmol) wasadded dropwise over a 10 min period. The solution was stirred at -78° C.for 30 min. A solution of 1-cyano-3,4-dihydronaphthalene (5 g, 32.2mmol), the product of Step 1 of Example 9, in 10 mL of THF was thenadded over a 10 min period. The reaction mixture was stirred at -78° C.,allowed to warm to ambient temperature and the reaction was quenched atambient temperature by the addition of concentrated ammonium chloride.The organic layer was dried over anhydrous magnesium sulfate, filteredand concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluted with hexane:ethyl acetate (10:1) togive 5 g (90% yield) of the title compound as a mixture ofdiastereomers.

Step 2: cis-1,2,3,4,4a,5,6,10b-Octahydro-3-oxo-benz[f]isoquinoline

Ethyl (1-cyano-1,2,3,4-tetrahydronaphthyl-2-yl)acetate (5 g, 20.5 mmol),from Step 1, was dissolved in 300 mL of ethyl alcohol. Raney nickel(16.6 g) was added and the reaction mixture was heated to 60° C. andshaken under 4 atmospheres of hydrogen for 24 h. The filtrate wasconcentrated in vacuo. The residue was adsorbed onto silica gel andchromatographed on silica gel eluted with ethyl acetate:water:formicacid (200:1:1) followed by ethyl acetate:water:formic acid (100:1:1) togive 3.2 mg (78% yield) of the title compound as a 1:1 mixture of thecis and trans isomers.

Step 3:cis-2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-3-oxo-benz[f]isoquinoline

cis-1,2,3,4,4a,5,6,10b-Octahydro-3-oxo-benz[f]isoquinoline (3.12 g, 15.5mmol), from Step 2, was dissolved in 100 mL of dry THF and potassiumt-butoxide (2.1 g, 18.6 mmol) was added. The reaction mixture wasstirred at ambient temperature for 3 h and then cooled to -78° C. Methyliodide (5 mL, 80.3 mmol) was added. The reaction mixture was allowed towarm to ambient temperature and stirred for 15 minutes and thenconcentrated in vacuo. The residue was chromatographed on silica geleluted with methylene chloride saturated with ammonia to afford 3.27 g(98% yield) of the title compound.

Step 4:cis-2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline

cis-2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-3-oxo-benz[f]isoquinoline(3.27 g (15.2 mmol) was dissolved in 60 mL of THF and the resultantsolution was cooled to 0° C. Benzyl magnesium chloride (11.4 mL of a2.0M solution in THF, 22.8 mmol), commercially available from AldrichChemical Company, was added and the reaction mixture was stirred at 0°C. for 1 h. Trifluoroacetic acid (0.5 mL) was added and then thereaction mixture was concentrated in vacuo. Methanol (50 mL) was added,followed by methanolic hydrochloric acid until the pH of the solutionwas between 1 and 3. A solution of sodium cyanoborohydride (2.86 g, 45.6mmol) in 25 mL of methanol was then added slowly. The pH of the reactionmixture was maintained between 1 and 3 by the addition of methanolichydrochloric acid. The solvent was removed in vacuo and the residue waspartitioned between 1N aqueous sodium hydroxide solution and methylenechloride (1:4 ). The aqueous layer was extracted with 2×200 mL ofmethylene chloride. The combined organic layers were dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel eluted withhexane:ethyl acetate (2:1) saturated with ammonia to give the titlecompound as two isomeric products: (71-4A) was the first compound toelute from the column; MS DCl--NH₃ M/Z: 292 (M+1)⁺ ; ¹ H NMR (CDCl₃)δ1.01-1.98 (5H, m), 2.24-2.72 (6H, m), 2.78-3.44 (5H, m), 6.80-7.35 (9H,m). Analysis calculated for C₂₁ H₂₅ N: C, 76.92; H, 7.99; N, 4.27.Found: C, 77.07; H, 8.04; N, 4.29. (71-4B) was the second compound toelute from the column; MS DCl--NH₃ M/Z: 292 (M+1)⁺ ; ¹ H NMR (CDCl₃)δ1.05-1.76 (5H, m), 2.08-2.29 (2H, m), 2.36-2.70 (2H, m), 2.56 (3H, m),2.77-2.89 (2H, m), 3.30 (1H, dd, J=4, 13 Hz), 3.61 (1H, dd, J=4, 13 Hz),7.03-7.40 (9H, m). Analysis calculated for C₂₁ H₂₅ N: C, 76.92; H, 7.99;N, 4.27. Found: C, 77.04; H, 8.12; N, 4.29.

EXAMPLE 72cis-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinolinehydrochloride Step 1:cis-8-Methoxy-1,3-dioxo-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline

n-Butyl lithium (8.1 mL, 20.196) was added to a solution of 3.9 mL(27.54 mmol) of diisopropylamine in 25 mL of THF at -78° C. A solutionof acetonitrile (1.01 mL, 18.54 mmol) in 10 mL of dry THF was then addeddropwise. The resultant solution was stirred at -78° C. for 1 h. Asolution of 1-cyano-6-methoxy-3,4-dihydronaphthalene (3.4 g, 18.36mmol), the product of Step 2 of Example 1, in 7 mL of THF was addeddropwise to the anion of acetonitrile and the reaction mixture wasstirred at -78° C. for 1 h. The reaction mixture was allowed to warm toambient temperature and the reaction was quenched with aqueous ammoniumchloride. The aqueous layer was extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was redissolved inmethylene chloride and adsorbed onto silica gel and chromatographed onsilica gel eluted with hexane/ethyl acetate (7:1) to give theintermediate acetonitrile adduct. The intermediate was dissolved in 100mL of methylene chloride and hydrogen bromide gas was bubbled into thesolution at 0° C. for 1 h. The methylene chloride was evaporated atambient temperature with a stream of nitrogen gas. The residue was addedto 50 mL of a 1:1 mixture of DMF and water. The reaction mixture wasthen heated at reflux overnight, allowed to cool to ambient temperatureand concentrated under reduced pressure. Water was added to the residueand the solid was collected by filtration. The solid was washed withwater and dissolved in methylene chloride. The methylene chloridesolution was washed with brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue (3.67 g) was dissolvedin 20 mL of dry THF and the solution was cooled to 0° C. under anitrogen atmosphere. Potassium t-butoxide (1.9 g, 16.5 mmol) was addedand the reaction mixture was stirred at ambient temperature for 1 h.Methyl iodide (1.12 mL, 18 mmol) was then added and the reaction mixturestirred for another hour at ambient temperature. The reaction wasquenched by the addition of saturated aqueous ammonium chloride. Theaqueous layer was diluted with water and extracted with ethyl acetate.The combined organic layers were dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give 1.54 g (34% overall yieldfrom the unsaturated nitrile) of the title compound.

Step 2:cis-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-1-oxo-3-phenylmethyl-benz[f]isoquinoline

cis-8-Methoxy-1,3-dioxo-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benz[f]isoquinoline(1.54 g, 5.9 mmol), from Step 1, was dissolved in 30 mL of THF/diethylether 1:1 and the resultant solution was cooled to 0° C. under anitrogen atmosphere. Benzyl magnesium bromide (4.45 g, 8.9 mmol) wasadded dropwise over a 20 min period. The reaction mixture was stirred at0° C. for 1 h and then 1 mL of trifluoroacetic acid (TFA) was added. Thereaction mixture was warmed to ˜30° C. and the solvent was evaporatedwith a stream of nitrogen gas. TFA (12 mL) was added to the residue andthe solution was cooled to 0° C. Sodium cyanoborohydride (1.12 g, 17.8mmol) was added in two portions and the reaction mixture was allowed towarm to ambient temperature. The reaction mixture was stirred at ambienttemperature for 3 h and the TFA was evaporated by passing a stream ofnitrogen through the reaction mixture overnight. The residue waspartitioned between methylene chloride and 1N aqueous hydrochloric acidsolution (4:1). The aqueous layer was extracted with two portions ofmethylene chloride. The combined methylene chloride layers were washedwith brine, dried over anhydrous magnesium sulfate, filtered andadsorbed onto silica gel. Chromatography sequentially with hexane ethylacetate in the following proportions; 2:1 followed by 1:1, 1:2, 1:4, and1:8) afforded 1.04 g of the title compound as a mixture of two isomers.

Step 3:cis-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinolinehydrochloride

8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-1-oxo-3-phenylmethyl-benz[f]isoquinoline(0.85 g, 2.53 mmol), from Step 2, was dissolved in 15 mL of dry THF and5.07 mL of a 1.0M solution of borane in THF (5.07 mmol) was added. Thereaction mixture was heated at reflux for 1 h under a nitrogen balloon.The THF was evaporated under reduced pressure. Methanol (30 mL) andmethanol saturated with hydrogen chloride (10 mL) were added to theresidue and the reaction mixture was heated at reflux for 1 h. Thesolvent was removed under reduced pressure and the residue waspartitioned between 1N aqueous sodium hydroxide solution and methylenechloride (1:4). The aqueous layer was extracted with two portions ofmethylene chloride. The combined organic layers were dried overanhydrous magnesium sulfate, filtered and adsorbed onto silica gel.Chromatography on silica gel eluted with hexane/diethyl ether saturatedwith ammonia (2:1) gave 0.55 g (68% yield) of the desired compound. Thehydrochloride salt was formed in diethyl ether saturated with hydrogenchloride. The hydrochloride salt was collected by filtration andcrystallized from acetone to afford the title compound, m.p. 202°-203.5°C.; MS DCl-isobutane M/Z: 322 (M+H)⁺, 378 (M+C₄ H₉)⁺ ; ¹ H NMR (CDCl₃)δ1.18-1.37 (2H, m), 1.61-1.70 (1H, m), 1.74-1.97 (2H, m), 2.17-2.32 (2H,m), 2.41 (3H, s), 2.47 (1H, dd, J=4, 13 Hz), 2.56-2.67 (1H, m),2.74-2.88 (2H, m), 3.16 (1H, d, J=9 Hz), 3.45 (1H, dd, J=4, 13 Hz), 3.78(3H, s), 6.62 (1H, d, J=2 Hz), 6.76 (1H, dd, J=2, 8 Hz), 7.10-7.30 (6H,m). Analysis calculated for C₂₂ H₂₈ ClNO: C, 73.83; H, 7.89; N, 3.91.Found: C, 73.76; H, 7.91; N, 3.85.

EXAMPLE 73cis-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinolinehydrochloride Step 1: Methyl3-oxo-4-phenyl-2-(1-cyano-6-methoxy-1,2,3,4-tetrahydronaphth-2-yl)-butyrate

Methyl 3-oxo-4-phenylbutyrate (29.33 g, 153 mmol) and1-cyano-6-methoxy-3,4-dihydronaphthalene (25.7, 139 mmol), the productof Step 2 of Example 1, were dissolved in 25 mL of acetonitrile. DBU(1.5 mL) was added and the reaction mixture was stirred for 2 h atambient temperature. A second aliquot of DBU (1.5 mL) was then added andstirring continued overnight. The reaction mixture was partitionedbetween diethyl ether and 1N aqueous hydrochloric acid solution (4:1)and the aqueous layer was extracted with diethyl ether. The combinedorganic layers were washed with 1N aqueous hydrochloric acid and brine,dried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was chromatographed on silica gel elutedwith hexane/ethyl acetate (6:1) to give 33.9 g (65% yield) of the titlecompound; MS DCl--NH₃ M/Z: 395 (M+NH₄)⁺.

Step 2:1-Cyano-6-methoxy-2-(2-oxo-3-phenylpropyl)-1,2,3,4-tetrahydronaphthalene

Methyl3-oxo-4-phenyl-2-(1-cyano-6-methoxy-1,2,3,4-tetrahydronaphth-2-yl)-butyrate(4.63 g, 12 mmol), from Step 1, was dissolved in 100 mL of methanol andlithium hydroxide (77 mL of a 1.0M solution) was added. The reactionmixture was stirred overnight at ambient temperature and then acidifiedwith 1N aqueous hydrochloric acid solution and extracted with diethylether. The ether extract was washed with brine, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Thebasic ether extract yielded 2.76 (70% yield) of the title compound; MSDCl--NH₃ M/Z: 337 (M+H)⁺.

Step 3:1-Cyano-2-[1-(1,3-dioxolane)-3-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphalene

Ethylene glycol (7 mL, 3 equivalents) was added to a solution of1-cyano-6-methoxy-2-(2-oxo-3-phenylpropyl)-1,2,3,4-tetrahydronaphthalene(11.8 g, 36.9 mmol), from step 2, in 250 mL of toluene.p-Toluenesulfonic acid (5 g) was added and the reaction mixture washeated at reflux for 5 h, cooled to ambient temperature, and thenpartitioned between 1N aqueous sodium hydroxide solution and diethylether (1:4). The aqueous layer was extracted with diethyl ether and thecombined organic layers were washed with water, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was chromatographed on silica gel eluted with hexane/ethylacetate (6:1) to give 8.2 g (61% yield) of the title compound; MSDCl--NH₃ M/Z: 364 (M+H)⁺ ; MS DCl--NH₃ M/Z: 381 (M+NH₄)⁺.

Step 4:1-Aminomethyl-2-[1-(1,3-dioxolane)-3-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphalene

1-Cyano-2-[1-(1,3-dioxolane)-3-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphalene(27.4 g, 75.4 mmol), from Step 3 hydrogenated over 55 g of Raney nickelin 50 mL of triethylamine and 450 mL of methanol, according to theprocedure described in Step 5 of Example 1. The reaction mixture wasfiltered and the filtrate concentrated in vacuo. The residue waspartitioned between 1N aqueous hydrochloric acid solution and methylenechloride (1:4). The layers were separated and the aqueous layer wasextracted with two portions of methylene chloride. The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to provide 24.8 g (90%yield) of the title compound which was carried on to the next step; MSDCl--NH₃ M/Z: 368 (M+H)⁺.

Step 5: cis and trans1-(N-t-Butyloxycarbonylamino)methyl-2-[1-(1,3-dioxolane)-3-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphalene

1-Aminomethyl-2-[1-(1,3-dioxolane)-3-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphalene(24.8 g, 67.5 mmol) was dissolved in 100 mL of DMF and the resultantsolution was cooled to 0° C. under nitrogen. BOC-anhydride (30 g, 135mmol) was added slowly and the reaction mixture was stirred for 1 h atambient temperature. The reaction mixture was partitioned betweendiethyl ether and water (5:1) and the aqueous layer was extracted withtwo portions of diethyl ether. The combined organic layers were washedtwice with water, once with brine, dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas chromatographed on silica gel eluted with hexane/diethyl ether (4:1and 2:1) to give a total of 30.4 g (96% yield) of two products. Thefirst compound to elute from the column (73-5A) was the cis isomer: MSDCl--NH₃ M/Z: 468 (M+H)⁺ ; MS DCl--NH₃ M/Z: 485 (M+NH₄)⁺. The secondcompound to elute from the column (73-5B) was the trans isomer: MSDCl--NH₃ M/Z: 468 (M+H)⁺ ; MS DCl--NH₃ M/Z: 485 (M+NH₄)⁺.

Step 6:cis-8-Methoxy-1,2,3,4,4a,5,6,10b-oxtahydro-3-phenylmethyl-benz[f]isoquinoline

cis-1-(N-t-Butyloxycarbonylamino)methyl-2-[1-(1,3-dioxolane)-3-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphalene(73-5A; 8.6 g, 18.4 mmol) was dissolved in 50 mL of methylene chlorideand trifluoroacetic acid (50 mL) was added. The reaction mixture wasstirred at ambient temperature for 0.5 h and then concentrated in vacuo.The residue was partitioned between cold 1N aqueous sodium hydroxidesolution and diethyl ether (1:5) and the aqueous layer was extractedwith two portions of diethyl ether. The combined organic layers weredried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure to give 5.5 g (98% yield) of the imine intermediate.The imine was dissolved in 100 mL of methanol and sodiumcyanoborohydride (3.5 g, 55 mmol) was added portionwise. Methanolichydrogen chloride was added to maintain the pH of the reaction mixtureat approximately 3. After the addition was complete, the reactionmixture was stirred at ambient temperature for 1 h and then acidifiedwith methanolic hydrogen chloride to quench the excess sodiumcyanoborohydride. The reaction mixture was concentrated under reducedpressure and the residue was partitioned between 1N aqueous sodiumhydroxide and methylene chloride (1:4). The aqueous layer was extractedwith two portions of methylene chloride and the combined organic layerswere dried over anhydrous magnesium sulfate, filtered and suspended onsilica gel. The product coated on silica gel was chromatographed onsilica gel eluted with ethyl acetate/water/formic acid (19:0.5:0.5followed by 18:1:1) to give the two diastereomeric title compounds in90% total yield (5 g). The first compound to elute from the column(73-6A) was the cis-anti isomer: MS DCl--NH₃ M/Z: 308 (M+H)⁺ ; ¹ H NMR(CDCl3) δ1.49-1.59 (m, 1H), 1.68-1.75 (m, 2H), 1.77 (bs, 1H), 2.01-2.21(m, 2H), 2.55 (dd, 1H, J=8, 14 Hz), 2.63-3.00 (m, 7H), 3.75 (s, 3H),6.59 (d, 1H, J=2 Hz), 6.67 (dd, 1H, J=2, 8 Hz), 7.00 (d, 1H, J=8 Hz),7.19-7.35 (m, 5H). The second compound to elute from the column (73-6B)was the cis-syn isomer; MS DCl--NH₃ M/Z: 308 (M+H)⁺ ; ¹ H NMR (CDCl3)δ1.06-1.20 (m, 1H), 1.38-1.47 (m, 1H), 1.64-1.74 (m, 1H), 1.81-1.95 (m,1H), 2.02-2.13 (m, 1H), 2.45 (dd, 1H, J=8, 14 Hz), 2.61-2.93 (m, 6H),2.96 (dd, 1H, J=4, 13 Hz), 3.74-3.82 (m, 1H), 3.79 (s, 3H), 6.65 (d, 1H,J=2 Hz), 6.77 (dd, 1H, J=2, 8 Hz), 7.11-7.31 (m, 6H).

Step 7:1-(N-(+)-Menthylcarbonylamino)methyl-2-[(1-(1,3-dioxolane)-3-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphalene

cis/anti-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline(73-6A; 1.0 g, 3.3 mmol) was dissolved in 25 mL of methylene chlorideand the resultant solution was cooled to 0° C. under nitrogen.Triethylamine (0.91 mL, 6.5 mmol) was added, followed by (+) menthylchloroformate (1.05 mL, 4.9 mmol) and the reaction mixture was stirredovernight at ambient temperature under a nitrogen atmosphere. Thereaction mixture was then partitioned between 1N aqueous sodiumhydroxide solution and diethyl ether (1:5). The organic layer was driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was chromatographed on silica gel elutedwith hexane/diethyl ether (5:1). The first compound to elute from thecolumn (73-7A) was recrystallized from methylene chloride/hexane to give(3S, 4aR, 10aS) isomer of the title compound:; MS DCl--NH₃ M/Z: 490(M+H)⁺ ; MS DCl--NH₃ M/Z: 507 (M+NH₄).sup. +. The second compound toelute from the column was a mixture of the (3S, 4aR, 10aS) isomer andthe (3R, 4aS, 10aR) isomer of the title compound. In order to obtain the(3S, 4aR, 10aS) isomer the above reaction was repeated using (-) menthylchloroformate to give the desired isomer as the first compound to elutefrom the column (73-7B) in 38% yield (0.62 g).

Step 8: (+) and (-)cis-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinolinehydrochloride

To a solution of1-(N-(+)menthylcarbonylamino)methyl-2-[1-(1,3-dioxolane)-3-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphalene(73-7A: 570 mg, 1.2 mmol) in 50 mL of THF was added lithium aluminumhydride (220 mg, 5.8 mmol) and the reaction mixture was heated to refluxunder nitrogen. The reaction mixture was heated at reflux for 2 h andthen cooled to 0° C. The reaction was quenched by the careful sequentialaddition of 250 μL of water, 250 μL of 4N aqueous sodium hydroxidesolution and 750 μL of water and stirred for 1 h at ambient temperature.The suspension was filtered, the solid was washed with THF and thefiltrate was concentrated in vacuo. The residue was suspended in silicagel and chromatographed on silica gel eluted with ethylacetate/water/formic acid (18:1:1). The product was partitioned between1N aqueous sodium hydroxide and ethyl acetate (1:4) and the ethylacetate solution was dried over anhydrous magnesium sulfate, filteredand concentrated to give the free amine of the title compound. The freeamine product was converted to its hydrochloride salt which isrecrystallized from acetone/diethyl ether to give the title compound(73-8A), m.p. 198°-199° C.; [α]_(D) ²³ -22.4° (c 1.16; CH₃ OH); MSDCl--NH₃ M/Z: 322 (M+H)⁺. Analysis calculated for C₂₂ H₂₈ ClNO: C,73.83; H, 7.89; N, 3.91. Found: C, 73.62; H, 7.85; N, 3.86.

The above procedure was repeated for 73-7B to give the (+) isomer of thetitle compound: [α]_(D) ²³ +22.4° (c 1.16; CH₃ OH); MS DCl--NH₃ M/Z: 322(M+H)⁺. Analysis calculated for C₂₂ H₂₈ ClNO: C, 73.83; H, 7.89; N,3.91. Found: C, 72.96; H, 7.76; N, 3.83.

EXAMPLE 74trans8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinolinehydrochloride Step 1:trans/syn-8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline

A solution of1-(N-t-butyloxycarbonylamino)methyl-2-[1-(1,3-dioxolane)-3-phenylethyl]-6-methoxy-1,2,3,4-tetrahydronaphalene,(73-5B; 19.1 g, 40.9 mmol) in 100 mL of methylene chloride was cooled to0° C. and trifluoroacetic acid (50 mL) was added. The reaction mixturewas stirred at ambient temperature for 1 h and then concentrated underreduced pressure. The residue was partitioned between 1N aqueous sodiumhydroxide solution and diethyl ether (1:5) and the aqueous layer wasextracted with three portions of diethyl ether. The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfate,filtered and suspended on silica gel. The product adsorbed on silica gelwas chromatographed on silica gel eluted with ethyl acetate/water/formicacid (28:1:1) to give 7.1 g of the intermediate trans imine as the firstcompound to elute from the column. The imine was dissolved in 200 mL ofmethanol and sodium cyanoborohydride (4.4 g, 70 mmol) was addedportionwise, maintaining the pH of the reaction mixture at approximately3 using methanolic hydrogen chloride. After the addition was complete,the reaction mixture was stirred for 0.5 h and concentrated in vacuo.The residue was partitioned between methylene chloride and 1N aqueoussodium hydroxide solution (4:1) and the aqueous layer was extracted withtwo portions of methylene chloride. The combined organic layers werewashed with brine, dried over anhydrous magnesium sulfate, filteredthrough Celite® filter aid and concentrated under reduced pressure togive 6.9 g (97% yield) of the trans-syn product; MS DCl--NH₃ M/Z: 308; ¹H NMR (CDCl3) δ1.12-1.29 (m, 1H), 1.32-1.47 (m, 1H), 1.47-1.63 (m, 1H),1.70-1.85 (m, 2H), 2.40-2.50 (m, 2H), 2.62-3.01 (m, 8H), 3.67-3.74 (m,1H), 3.76 (s, 3H), 6.73 (d, 1H, J=2 Hz), 6.78 (dd, 1H, J=2, 8 Hz), 7.06(d, 1H, J=8 Hz), 7.19-7.36 (m, 5H).

Step 2: (-)trans8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinolinehydrochloride

Following the procedure described above in Step 7 of Example 73, theproduct of Step 1 of this Example was treated with (+) menthylchloroformate to give the desired diastereomeric carbamates. Thecarbamate was reduced by the procedure described in Step 8 of Example 73to afford the (-) isomer of the title compound as the first compound toelute from the column: m.p. 218.5°-221° C.; [α]_(D) ²³ -47.8° (c 0.965;CH₃ OH). Analysis calculated for C₂₂ H₂₈ ClNO: C, 73.83; H, 7.89; N,3.91. Found: C, 73.62; H, 7.78; N, 4.01.

EXAMPLE 752-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride Step 1:2-(2-Ethoxycarbonylethyl)-3,4-dihydro-1(2H)-naphthalenone

α-Tetralone (20 g, 137 mmol), commercially available from AldrichChemical Company, was combined with 200 mL of toluene, 30 mL ofpyrrolidine and a catalytic amount of p-toluenesulfonic acid and thereaction mixture was heated at reflux for 4 days. The reaction mixturewas concentrated in vacuo and 300 mL of absolute ethyl alcohol and 25 mLof ethyl acrylate were added to the residue. The reaction mixture washeated at reflux for 3 h and then 100 mL of water was added and refluxcontinued for 1 h. The reaction mixture was concentrated in vacuo andthe residue was partitioned between dilute aqueous hydrochloric acid andethyl acetate (1:5). The organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel eluted with 10% ethyl acetatein hexane to give 19.7 g (59% yield) of the title compound; MS DCl--NH3M/Z: 247 (M+H)⁺, 264 (M+NH₄)⁺.

Step 2: 1-Cyano-2-(2-ethoxycarbonylethyl)-3,4-dihydronaphthalene

2-(2-Ethoxycarbonylethyl)-3,4-dihydro-1(2H)-naphthalenone (19.7 g, 80mmol), from Step 1, was dissolved in 200 mL of dry THF and diethylcyanophosphonate (23.6 mL, 160 mmol), commercially available fromAldrich Chemical Company, was added, followed by 160 mL of a 0.5Msolution of lithium cyanide in DMF. The reaction mixture was stirred atambient temperature overnight and then poured into water. The aqueousmixture was extracted with three portions of diethyl ether. The etherextracts were dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was dissolved in 400 mLof toluene and 20 g of p-toluenesulfonic acid was added. The reactionmixture was heated at reflux for 3 h and allowed to cool to ambienttemperature. The toluene solution was washed with 5% aqueous sodiumbicarbonate, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel eluted with 10% ethyl acetate in hexane to give 13.1 g (64.2%yield) of the title compound; MS DCl--NH3 M/Z: 273 (M+NH₄)⁺.

Step 3: 1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine

1-Cyano-2-(2-ethoxycarbonylethyl)-3,4-dihydronaphthalene (13 g, 51 mmol)was dissolved in 300 mL of ethyl alcohol. Raney nickel #28 (26 g) wasadded and the reaction mixture was heated to 50° C. and shaken under 4atmospheres of hydrogen for 18 h. The catalyst was removed by filtrationand the filtrate was concentrated in vacuo. Ethyl acetate/hexane (1:1)was added to the residue and a solid precipitated. The solid wascollected by filtration to give 2.53 g of the cis isomer of the productas white crystals, m.p. 210° C.; MS DCl--NH3 M/Z: 216 (M+H)⁺, 233(M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ155-2.13 (4H, m), 2.2-2.46 (2H, m),2.58-2.73 (1H, m), 2.74-3.2 (4H, m), 3.62-3.77 (1H, m), 5.9 (1H, bs),7.03-7.33 (4H, m).

The filtrate was concentrated in vacuo and 150 mL of xylene and acatalytic amount of p-toluenesulfonic acid were added to the residue.The resultant solution was heated at reflux overnight. The solvent wasevaporated and the residue was triturated with ethyl acetate/hexane(1:1) to give 6 g (55% yield) of the trans isomer of the product aswhite crystals, m.p. 154°-156° C.; MS DCl--NH3 M/Z: 216 (M+H)⁺, 233(M+NH₄)⁺ 1 H NMR (CDCl₃) δ1.46-1.76 (4H, m), 1.78-2.02 (2H, m),2.52-3.02 (4H, m), 3.33-3.44 (1H, m), 3.73-3.84 (1H, m), 6.08 (1H, bs),7.07-7.35 (4H, m).

Step 4:cis-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine

cis-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine(2.53 g, 11.76 mmol), from Step 3, was suspended in 50 mL of dry THF and1.98 g of potassium t-butoxide was added. The reaction mixture wasstirred at ambient temperature for 0.5 h and then 2.5 mL of methyliodide was added. The reaction mixture was stirred at ambienttemperature for 1 h and then it was poured into water. The aqueousmixture was extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous magnesium sulfate, filteredand concentrated in vacuo to give 2.35 g (87% yield) of the titlecompound, m.p. 130°-131° C.; MS DCl--NH3 M/Z: 230 (M+H)⁺, 247 (M+NH₄)⁺.

Step 5:cis-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride

2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine(1.37 g, 6 mmol), from Step 4, was dissolved in 30 mL of 1:1 THF:diethylether and the resultant solution was cooled to 0° C. Benzylmagnesiumbromide (4.55 mL of a 2.0M solution in THF, 1.5 equivalents),commercially available from Aldrich Chemical Company, was added and thereaction mixture was stirred at 0° C. for 45 min. The reaction was thenquenched by the addition of saturated aqueous ammonium chloride and theaqueous mixture was extracted with methylene chloride. The organic layerwas dried over anhydrous magnesium sulfate, filtered and concentratedunder reduced pressure. The residue was dissolved in methanol and 1.5 gof sodium cyanoborohydride was added portionwise. The pH of the reactionmixture was adjusted to 5 by the addition of methanol saturated withhydrogen chloride. After 20 min the pH was again adjusted to 5 by theaddition of methanol saturated with hydrogen chloride. After 2 h,methanol was added to quench the excess sodium cyanoborohydride. Thesolvent was evaporated in vacuo and the residue was partitioned between2N sodium hydroxide and methylene chloride. The methylene chloridesolution was dried over anhydrous magnesium sulfate, filtered andevaporated under reduced pressure. The residue was purified bychromatography on silica gel eluted with 10% ethyl acetate in hexanesaturated with ammonium hydroxide to give a total of 1.13 g (62% yield)of the two isomeric products which were converted to their hydrochloridesalts in diethyl ether saturated with hydrogen chloride.

The first compound to elute from the column (75A) was 0.28 g of thecis/syn isomer, m.p. 125°-128° C.; MS DCl--NH3 M/Z: 306 )M+H)⁺ ; ¹ H NMR(CDCl₃) δ1.42-1.93 (6H, m), 2.0-2.12 (1H, m), 2.37-2.52 (1H, m), 2.58(1H, d, J=18.0 Hz), 2.7 (3H, s), 2.75-2.93 (4H, m), 3.12-3.22 (1H, m),3.25-3.37 (1H, m), 7.02-7.32 (9H, m). Analysis calculated for C₂₂ H₂₈ClN+0.25H₂ O: C, 76.30; H, 8.09; N, 4.04. Found: C, 76.27; H, 7.66; N,4.07.

The second compound to elute from the column (75B) was the cis/antiisomer (0.85 g), m.p. 228°-230° C.; MS DCl--NH3 M 306 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ1.3-1.74 (5H, m), 1.92-2.04 (2H, m), 2.35-2.6 (3H, m), 2.6 (3H,s), 2.76-2.89 (2H, m), 2.96-3.0 (2H, m), 3.23-3.31 (1H, m), 3.81 (3H,s), 6.65 (1H, d, J=9 Hz), 6.9 (1H, d, J=9 Hz), 7.1-7.33 (9H, m).Analysis calculated for C₂₂ H₂₈ ClN: C, 77.31; H, 8.09; N, 4.10. Found:C, 77.22; H, 8.32; N, 4.01.

EXAMPLE 768-Methoxy-2-methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride Step 1:2-(2-Ethoxycarbonylethyl)-3,4-dihydro-5-methoxy-1(2H)-naphthalenone

5-Methoxy-α-Tetralone (20 g, 113 mmol), commercially available fromAldrich Chemical Company, was combined with 400 mL of toluene, 30 mL ofpyrrolidine and a catalytic amount of p-toluenesulfonic acid and thereaction mixture was heated at reflux over molecular sieves for 72. Thereaction mixture was concentrated in vacuo and 300 mL of absolute ethylalcohol and 20 mL of ethyl acrylate were added to the residue. Thereaction mixture was heated at reflux for 4 h and then 100 mL of waterwas added and reflux continued for 1 h. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between diluteaqueous hydrochloric acid and ethyl acetate (1:5). The organic layer wasdried over anhydrous magnesium sulfate, filtered and concentrated invacuo. The residue was purified by chromatography on silica gel elutedwith 10% ethyl acetate in hexane to give 14.37 g (46% yield) of thetitle compound; MS DCl--NH3 M/Z: 277 (M+H)⁺, 294 (M+NH₄)⁺.

Step 2:1-Cyano-2-(2-ethoxycarbonylethyl)-5-methoxy-3,4-dihydronaphthalene

2-(2-Ethoxycarbonylethyl)-3,4-dihydro-5-methoxy-1(2H)-naphthalenone (1.1g, 4 mmol), from Step 1, was dissolved in 15 mL of dry THF and cooled to0° C. Diethyl cyanophosphonate (1.18 mL, 8 mmol), commercially availablefrom Aldrich Chemical Company, was added, followed by 8 mL of a 0.5Msolution of lithium cyanide (4 mmol) in DMF. The reaction mixture wasstirred at ambient temperature overnight and then poured into water. Theaqueous mixture was extracted with three portions of diethyl ether/ethylacetate. The organic extracts were washed with brine, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The residue was dissolved in 100 mL of toluene and 1.1 g ofp-toluenesulfonic acid was added. The reaction mixture was heated atreflux for 2 h and allowed to cool to ambient temperature. The toluenesolution was poured into 5% aqueous sodium bicarbonate and the aqueousmixture was extracted with ethyl acetate. The combined organic layerswere dried over anhydrous magnesium sulfate, filtered and concentratedin vacuo. The residue was purified by chromatography on silica geleluted with 10% ethyl acetate in hexane to give 0.8 g (70% yield) of thetitle compound; MS DCl--NH3 M/Z: 286 (M+H)⁺, 303 (M+NH₄)⁺.

Step 3:8-Methoxy-2-methyl-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine

1-Cyano-2-(2-ethoxycarbonylethyl)-5-methoxy-3,4-dihydronaphthalene (9.8g, 34.39 mmol) was dissolved in 250 mL of ethyl alcohol. Raney nickel(19.6 g) was added and the reaction mixture was heated to 50° C. andshaken under 4 atmospheres of hydrogen for 18 h. The catalyst wasremoved by filtration and the filtrate was concentrated in vacuo. 20%Ethyl acetate in hexane was added to the residue and a solidprecipitated. The solid was collected by filtration to give 2.6 g ofwhite crystals. The filtrate was concentrated in vacuo and xylene and acatalytic amount of p-toluenesulfonic acid were added to the residue.The resultant solution was heated at reflux for 16 h. The solvent wasevaporated in vacuo and the residue was crystallized from ethylacetate/hexane (1:1) to give 2.72 g of white crystals, m.p. 182°-184°C.; MS DCl--NH3 M/Z: 246 (M+H)⁺, 263 (M+NH₄)⁺. The crystals werecombined (62% total yield) and carried on to the next step.

Step 4:8-Methoxy-2-methyl-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine

8-Methoxy-2-methyl-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine(5.31 g, 21.67 mmol), from Step 3, was suspended in 100 mL of dry THFand 3.64 g (1.5 equivalents) of potassium t-butoxide was added. Thereaction mixture was stirred at ambient temperature for 0.5 h and then 5mL of methyl iodide was added. The reaction mixture was stirred atambient temperature for 1 h and then it was poured into water. Theaqueous mixture was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give 5.25 g (94% yield) of thetitle compound, m.p. 123°-124° C.; MS DCl--NH3 M/Z: 260 (M+H)⁺, 277(M+NH₄)⁺.

Step 5:8-Methoxy-2-methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride

8-Methoxy-2-methyl-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine(0.51 g, 2 mmol), from Step 4, was dissolved in 50 mL of 1:1 THF:diethylether and the resultant solution was cooled to 0° C. Benzylmagnesiumbromide (1.5 mL of a 2.0M solution in THF, 1.5 equivalents),commercially available from Aldrich Chemical Company, was added and thereaction mixture was stirred at 0° C. for 1.5 h. The reaction was thenquenched by the addition of saturated aqueous ammonium chloride and theaqueous mixture was extracted with methylene chloride. The organic layerwas dried over anhydrous magnesium sulfate, filtered and concentratedunder reduced pressure. The residue was dissolved in methanol and 0.9 gof sodium cyanoborohydride was added portionwise. The pH of the reactionmixture was adjusted to 5 by the addition of methanol saturated withhydrogen chloride. After 10 min the pH was again adjusted to 5 by theaddition of methanol saturated with hydrogen chloride. After 2 h at 0°C., methanol was added to quench the excess sodium cyanoborohydride. Thesolvent was evaporated in vacuo and the residue was partitioned between1N aqueous sodium hydroxide and methylene chloride (1:5). The methylenechloride solution was dried over anhydrous magnesium sulfate, filteredand evaporated under reduced pressure. The residue (0.82 g) was purifiedby chromatography on silica gel eluted with 10% ethyl acetate in hexanesaturated with ammonium hydroxide to give a total of 0.82 g (62% yield)of the two isomeric products which were converted to their hydrochloridesalts in diethyl ether saturated with hydrogen chloride. The firstcompound to elute from the column (76A) was 0.08 g of the cis/synisomer; MS DCl--NH3 M/Z: 336 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.42-1.87 (6H,m), 1.95-2.07 (1H, m), 2.37-2.52 (2H, m), 2.61 (1H, d, J=18.0 Hz), 2.7(3H, s), 2.75-2.93 (3H, m), 3.11-3.18 (1H, m), 3.27-3.37 (1H, m), 3.81(3H, s), 6.64 (1H, d, J=9 Hz), 6.75 (1H, d, J=9 Hz), 7.09-7.2 (6H, m).Analysis calculated for C₂₃ H₂₉ ClNO: C, 74.29; H, 8.07; N, 3.774.Found: C, 74.13; H, 8.21; N, 3.67. The final compound to elute from thecolumn was the cis/anti isomer (76B); MS DCl--NH3 M/Z: 336 (M+H)⁺ ; ¹ HNMR (CDCl₃) δ1.34-1.74 (5H, m), 1.92-2.12 (2H, m), 2.49-2.63 (4H, m),2.6 (3H, s), 2.69-2.84 (3H, m), 2.96-3.12 (2H, m), 3.24-3.33 (1H, m),7.03-7.34 (9H, m). Analysis calculated for C₂₃ H₂₉ ClNO+0.25H₂ O: C,73.40; H, 7.98; N, 3.72. Found: C, 73.45; H, 8.15; N, 3.65.

EXAMPLE 77(+)-cis-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride Step 1:cis-2-Benzyl-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine

To a suspension ofcis-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine (1.0 g,4.65 mmol), from Step 3 of Example 75, in 20 mL of dry THF, was addedpotassium t-butoxide (0.78 g, 6.9 mmol). The reaction mixture wasstirred at ambient temperature for 0.5 h and then cooled to 0° C. andbenzyl bromide (0.8 mL, 6.7 mmol) was added. The reaction mixture wasallowed to warm to ambient temperature, stirred for 3 h and then pouredinto water and extracted three times with ethyl acetate. The combinedorganic layers were dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The residue was crystalized from ether/hexane toafford 1.1 g (79% yield) of the title compound, m.p. 114°-115° C.; MSDCl--NH₃ M/Z: 306 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.5-2.2 (5H, m), 2.42-2.54(1H, m), 2.58-3.03 (5H, m), 3.79 (1H, dd, J=9.5, 13.6 Hz), 4.44 (1H, d,J=13.6 Hz), 4.95 (1H, d, J=13.6 Hz), 6.47-6.5 (1H, m), 6.97-7.45 (8H,m).

Step 2:cis-2-Benzyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride

cis-2-Benzyl-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine(3.5 g, 11.48 mmol), from Step 1, was dissolved in 60 mL of THF and theresultant solution was cooled to 0° C. Benzyl magnesium chloride (11.4mL of a 2.0M solution in THF, 22.8 mmol), commercially available fromAldrich Chemical Company, was added and the reaction mixture was stirredat 0° C. for 2 h. The reaction was quenched by the addition of ammoniumchloride and the reaction mixture was extracted with methylene chloride.The combined methylene chloride extract was dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. Methanol (50 mL)was added, followed by sodium cyanoborohydride (2.4 g, 39 mmol), addedportionwise. The pH of the reaction mixture was maintained between 3 and5 by the addition of methanolic hydrochloric acid. The reaction mixturewas stirred overnight. The solvent was removed in vacuo and the residuewas partitioned between 1N aqueous sodium hydroxide solution and ethylacetate (1:4). The aqueous layer was extracted with 2×200 mL of ethylacetate. The combined organic layers were dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel eluted with hexane/ethyl acetate (40:1) togive the title compound. The product was crystallized from ethanol, m.p.232°-233° C.; MS DCl--NH₃ M/Z: 382 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.47-1.86(5H, m), 1.98-2.1 (2H, m), 2.63-2.93 ( 6H, m), 3.05-3.15 (2H, m), 3.6(1H, d, J=13.6 Hz), 4.12 (1H, d, J=13.6 Hz), 6.57-6.63 (1H, d, J=6.8Hz), 6.89-7.4 (13H, m). Analysis calculated for C₂₀ H₃₂ ClN: C, 80.48;H, 7.66; N, 3.35. Found: C, 80.51; H, 7.95; N, 3.28.

Step 3:cis-1,3,4,5,5a,6,7,11b-Octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride

cis-2-Benzyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride (2.75 g, 6.58 mmol), from Step 2, was dissolved in 150 mLof methanol and hydrogenated (4 atmospheres H₂) over 20% palladium oncarbon (0.3 g) at ambient temperature for 24 h. The catalyst was removedby filtration and the filtrate was concentrated under reduced pressureto give 1.65 g (77% yield) of the title compound, which was used in thenext step without purification.

Step 4:cis-2-((-)-Menthyloxycarbonyl)-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine

To a solution ofcis-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride (1.3 g, 4.47 mmol) in 50 mL of methylene chloride wasadded (-) menthylchloroformate (1.47 g, 6.72 mmol) (commerciallyavailable from Aldrich Chemical Company) and 1.1 mL of pyridine. Thereaction mixture was stirred at ambient temperature for 1 h and then itwas poured into water. The organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue waschromatographed on silica gel eluted with hexane/diethyl ether (20:1) togive the title compound as two diastereomers. The first diastereomericcompound (4A) to be eluted from the column was collected in 43% yield(0.9 g). The second compound to be eluted from the column (0.9 g) wasrechromatographed on silica gel eluted with hexane/diethyl ether (30:1)to afford 0.68 g (33% yield) of the other diastereomer (4B).

Step 5: (+) cis-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine hydrochloride

cis-2-((-)-Methyloxycarbonyl)-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine(0.7 g, 1.48 mmol), from Step 4--compound 4A), was dissolved in 70 mL oftoluene. To the resultant solution was added 0.58 g (14.8 mmol) oflithium aluminum hydride and the reaction mixture was heated at refluxfor 1.5 h. The reaction mixture was cooled to 0° C. and the reaction wasquenched by the sequential addition of 0.58 mL of water, 0.58 mL of 15%aqueous sodium hydroxide solution and 1.74 mL of water. The resultantgranular precipitate was stirred at ambient temperature for 1 h and thenfiltered through a pad of Celite® filter aid. The filtrate wasconcentrated and then converted to the hydrochloride salt by treatmentwith hydrogen chloride in diethyl ether. The solid was filtered andcrystallized from ethanol/water to give the title compound, m.p.205°-207° C.; MS DCl--NH₃ M/Z: 306 (M+H)⁺ ; .sup. 1 H NMR (CDCl₃)δ1.32-1.76 (6H, m), 1.92-2.1 (2H, m), 2.47-2.87 (7H, m), 2.95-3.15 (2H,m), 3.24-3.35 (1H, m), 7.01-7.37 (9H, m). Analysis calculated for C₂₂H₂₈ ClN.0.5H₂ O: C, 75.32; H, 8.27; N, 3.99. Found: C, 75.78; H, 8.35;N, 4.17.

EXAMPLE 78 (-)2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride

Following the procedures described in Step 5 of Example 77, compound 4Bfrom Step 4 of Example 77 was reduced to afford the title compound. Thetitle compound was recrystallized from acetone/diethyl either to give0.2 g of pure title compound, m.p. 206°-208° C.; MS DCl--NH₃ M/Z: 306(M+H)⁺ ; ¹ H NMR (CDCl₃) δ1.32-1.76 (6H, m), 1.92-2.1 (2H, m), 2.47-2.87(7H, m), 2.95-3.15 (2H, m), 3.24-3.35 (1H, m), 7.01-7.37 (9H, m).Analysis calculated for C₂₂ H₂₈ ClN.0.5H₂ O: C, 77.30; H, 8.20; N, 4.04.Found: C, 77.05; H, 8.27; N, 4.04.

EXAMPLE 79trans-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride Step 1: trans-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine

Following the procedures described in Step 4 of Example 75. The transisomer of the product of Step 3 of Example 75 (2.5 g, 11.5 mmol) wasmethylated to give 2.47 g (94% yield) of the title compound as anoff-white solid.

Step 2:trans-2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride

Following the procedures described in Step 5 of Example 75,trans-2-methyl-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine,from Step 1 above, was converted to a total of 1.82 g (65% yield) of twoisomeric products which were converted to their hydrochloride salts indiethyl ether saturated with hydrogen chloride.

The first compound to elute from the column (78A) was 988 mg of thetrans/syn isomer, m.p. 213°-215° C.; MS DCl--NH₃ M/Z: 306 (M+H)⁺.Analysis calculated for C₂₂ H₂₈ ClN: C, 77.28; H, 8.25; N, 4.10. Found:C, 77.25; H, 8.19; N, 4.01.

The second compound to elute from the column was rechromatographed onsilica gel eluted with 10% ethyl acetate in hexane saturated withammonium hydroxide and converted to the hydrochloride salt in diethylether to give (78B) the trans/anti isomer (483 mg), m.p. 186°-187° C.;MS DCl--NH₃ M/Z: 306 (M+H)⁺. Analysis calculated for C₂₂ H₂₈ ClN: C,77.28; H, 8.25; N, 4.10. Found: C, 76.90; H, 8.20; N, 4.02.

EXAMPLES 80-105

By following the synthetic methods outlined in reaction scheme I A andreaction scheme I B, the following compounds (Example 80-105) can beprepared starting with 6-trifluoromethyl-α-tetralone or7-trifluoromethyl-α-tetralone (B. R. Vogt, U.S. Pat. No. 4,051,248,issued Sep. 27, 1977) and using the procedures described in the citedexamples.

Examples 80-85 listed below are prepared in accordance with theprocedures described in Examples 1, 2 and 3.

80) cis/trans2,3,3a,4,5,9b-Hexahydro-3-phenylmethyl-6-trifluoromethyl-1H-benz[e]isoindolehydrochloride;

81)cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-6-trifluoromethyl-1H-benz[e]isoindolemethanesulfonic acid salt;

82)cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-6-trifluoromethyl-1H-benz[e]isoindolemethanesulfonate salt;

83) cis/trans2,3,3a,4,5,9b-Hexahydro-3-phenylmethyl-7-trifluoromethyl-1H-benz[e]isoindolehydrochloride;

84)cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-7-trifluoromethyl-1H-benz[e]isoindolemethanesulfonic acid salt;

85)cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-phenylmethyl-7-trifluoromethyl-1H-benz[e]isoindolemethanesulfonate salt.

Examples 86-89 listed below are prepared in accordance with theprocedures described in Examples 6 and 7.

86)trans-2,3,3a,4,5,9b-Hexahydro-3-phenylmethyl-6-trifluoromethyl-1H-benz[e]isoindolemethanesulfonic acid salt;

87)trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-6-trifluoromethyl-1H-benz[e]isoindole;

88)trans-2,3,3a,4,5,9b-Hexahydro-3-phenylmethyl-7-trifluoromethyl-1H-benz[e]isoindolemethanesulfonic acid salt;

89)trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-phenylmethyl-7-trifluoromethyl-1H-benz[e]isoindole.

Examples 90-95 listed below are prepared in accordance with theprocedures described in Examples 11, 12 and 13.

90)cis-2,3,3a,4,5,9b-Hexahydro-3-(3-methylphenyl)methyl-6-trifluoromethyl-1H-benz[e]isoindolehydrochloride;

91)cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-6-trifluoromethyl-1H-benz[e]isoindolehydrochloride;

92)cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-6-trifluoromethyl-1H-benz[e]isoindolehydrochloride;

93)cis-2,3,3a,4,5,9b-Hexahydro-3-(3-methylphenyl)methyl-7-trifluoromethyl-1H-benz[e]isoindolehydrochloride;

94)cis-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-7-trifluoromethyl-1H-benz[e]isoindolehydrochloride;

95)cis-2-Ethyl-2,3,3a,4,5,9b-hexahydro-3-(3-methylphenyl)methyl-7-trifluoromethyl-1H-benz[e]isoindolehydrochloride.

Examples 96 and 97 listed below are prepared in accordance with theprocedures described in Example 14.

96)trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-6-trifluoromethyl-1H-benz[e]isoindolemethanesulfonic acid salt;

97)trans-2,3,3a,4,5,9b-Hexahydro-2-methyl-3-(3-methylphenyl)methyl-7-trifluoromethyl-1H-benz[e]isoindolemethanesulfonic acid salt.

Examples 98-101 listed below are prepared in accordance with theprocedures described in Examples 15 and 16.

98)cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-trifluoromethyl-1H-benz[e]isoindolehydrochloride;

99)cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6-trifluoromethyl-1H-benz[e]isoindolehydrochloride;

100)cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-trifluoromethyl-1H-benz[e]isoindolehydrochloride;

101)cis-3-(3-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-7-trifluoromethyl-1H-benz[e]isoindolehydrochloride.

Examples 102-105 listed below are prepared in accordance with theprocedures described in Examples 17 and 18.

102)3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-6-trifluoromethyl-1H-benz[e]isoindolemethanesulfonic acid salt;

103)cis-3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-6-trifluoromethyl-1H-benz[e]isoindolemethanesulfonic acid salt;

104)3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-7-trifluoromethyl-1H-benz[e]isoindolemethanesulfonic acid salt;

105)cis-3-(4-Fluorophenyl)methyl-2,3,3a,4,5,9b-hexahydro-2-methyl-7-trifluoromethyl-1H-benz[e]isoindolemethanesulfonic acid salt.

                  TABLE 2                                                         ______________________________________                                        Results of uptake inhibition studies - IC.sub.50 (nM)                         Example No.   NE.sup.(1)                                                                              5-HT.sup.(2)                                                                            DA.sup.(3)                                  ______________________________________                                         1            524       7290      7620                                         2            58        4162      182                                          3            18        1396      225                                          6            543       6508      10100                                        7            322       12200     13400                                        8            120       2704      4700                                         9            48        6600      540                                         10            454       13500     6720                                        11            238       827       5143                                        12            37        1777      571                                         13            18        507       148                                         15            347       15000     7700                                        16            50        5450      441                                         17            665       11000     9200                                        18            241       2909      4822                                        21            758       13100     5490                                        22            60        3440      368                                         23            28        1432      141                                         24            104       2467      170                                         25            27        1900      197                                         26            603       2255      9040                                        27            189       2083      4590                                        28            78        1870      213                                         31            592       14000     5419                                        32            113       12705     169                                         36            62        964       952                                         38            261       3566      1331                                        47            41        1258      225                                         71A           9.8       2120      450                                         71B           11.9      2050      633                                         72            64        5750      1013                                        75A           30        227       444                                         75B           513       4130      2810                                        76A           3.5       386       529                                         76B           234       344       2190                                        77            189.7     4166      5169                                        78            9.7       <1000     189                                         ______________________________________                                         .sup.(1) NE = norepinephrine                                                  .sup.(2) 5-HT = 5hydroxytryptamine                                            .sup.(3) DA = dopamine                                                   

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

What is claimed is:
 1. A compound of the formula: ##STR32## wherein m is0, 1 or 2 and n is 0 or 1, but m and n are never both 0;R¹ is hydrogenor C₁ -C₆ -alkyl; R² is C₇ -C₁₆ -arylalkyl, wherein the aryl group isunsubstituted or substituted with from one-to-three non-hydrogen membersindependently selected from the group consisting of halogen, C₁ -C₆-alkyl, halo-C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy, hydroxy, amino and C₁ -C₆-alkylamino; R³, R⁴, R⁵ and R⁶ are independently selected from the groupconsisting of hydrogen, C₁ -C₆ -alkoxy, C₁ -C₆ -alkyl, halogen andhalo-C₁ -C₆ -alkyl, or any two of R³, R⁴, R⁵ and R⁶ taken together forma methylenedioxy group; and R⁷ is hydrogen, methyl or ethyl;or apharmaceutically-acceptable salt thereof.
 2. A compound according toclaim 1 wherein R¹ is hydrogen, methyl or ethyl.
 3. A compound accordingto claim 2 wherein m is 1, n is 0, R⁷ is hydrogen and R² is C₇ -C₁₆-arylalkyl, wherein the aryl group is unsubstituted or substituted withfrom one to three non-hydrogen members independently selected from thegroup consisting of halogen, C₁ -C₆ -alkyl, halo-C₁ -C₆ -alkyl, C₁ -C₆-alkoxy, hydroxy, amino and C₁ -C₆ -alkylamino.
 4. A compound accordingto claim 2 wherein m is 2, n is 0, R⁷ is hydrogen and R² is C₇ -C₁₆-arylalkyl, wherein the aryl group is unsubstituted or substituted withfrom one to three non-hydrogen members independently selected from thegroup consisting of halogen, C₁ -C₆ -alkyl, halo-C₁ -C₆ -alkyl, C₁ -C₆-alkoxy, hydroxy, amino and C₁ -C₆ -alkylamino.
 5. A compound selectedfrom:2-Methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline;8-Methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-3-phenylmethyl-benz[f]isoquinoline;2-Methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepine;and8-Methoxy-2-methyl-1,3,4,5,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride, and(-)-cis-2-Methyl-1,3,4,5a,6,7,11b-octahydro-3-phenylmethyl-2H-naphth[1,2-c]azepinehydrochloride;or a pharmaceutically-acceptable salt thereof.
 6. Apharmaceutical composition for treating affective disorders comprising atherapeutically-effective amount of a compound as defined in claim 1 anda pharmaceutically-acceptable carrier.
 7. A pharmaceutical compositionfor treating affective disorders comprising a therapeutically-effectiveamount of a compound selected from the compounds named in claim 5 and apharmaceutically-acceptable carrier.
 8. A method of treating affectivedisorders comprising administering to a patient in need of suchtreatment a therapeutically-effective amount of a compound as defined inclaim
 1. 9. A method of treating affective disorders comprisingadministering to a patient in need of such treatment atherapeutically-effective amount of a compound selected from thecompounds named in claim
 5. 10. A method according to claim 8 whereinthe affective disorder being treated is depression.